To see the other types of publications on this topic, follow the link: Pyruvate kinase M2 (PKM2).
Journal articles on the topic 'Pyruvate kinase M2 (PKM2)'
Create a spot-on reference in APA, MLA, Chicago, Harvard, and other styles
Consult the top 50 journal articles for your research on the topic 'Pyruvate kinase M2 (PKM2).'
Next to every source in the list of references, there is an 'Add to bibliography' button. Press on it, and we will generate automatically the bibliographic reference to the chosen work in the citation style you need: APA, MLA, Harvard, Chicago, Vancouver, etc.
You can also download the full text of the academic publication as pdf and read online its abstract whenever available in the metadata.
Browse journal articles on a wide variety of disciplines and organise your bibliography correctly.
1
Kurihara-Shimomura, Miyako, Tomonori Sasahira, Chie Nakashima, Hiroki Kuniyasu, Hiroyuki Shimomura, and Tadaaki Kirita. "The Multifarious Functions of Pyruvate Kinase M2 in Oral Cancer Cells." International Journal of Molecular Sciences 19, no. 10 (September 25, 2018): 2907. http://dx.doi.org/10.3390/ijms19102907.
Full textAbstract:
Head and neck cancers, including oral squamous cell carcinoma (OSCC), are the sixth most common malignancies worldwide. OSCC frequently leads to oral dysfunction, which worsens a patient’s quality of life. Moreover, its prognosis remains poor. Unlike normal cells, tumor cells preferentially metabolize glucose by aerobic glycolysis. Pyruvate kinase (PK) catalyzes the final step in glycolysis, and the transition from PKM1 to PKM2 is observed in many cancer cells. However, little is known about PKM expression and function in OSCC. In this study, we investigated the expression of PKM in OSCC specimens and performed a functional analysis of human OSCC cells. We found that the PKM2/PKM1 ratio was higher in OSCC cells than in adjacent normal mucosal cells and in samples obtained from dysplasia patients. Furthermore, PKM2 expression was strongly correlated with OSCC tumor progression on immunohistochemistry. PKM2 expression was higher during cell growth, invasion, and apoptosis in HSC3 cells, which show a high energy flow and whose metabolism depends on aerobic glycolysis and oxidative phosphorylation. PKM2 expression was also associated with the production of reactive oxygen species (ROS) and integration of glutamine into lactate. Our results suggested that PKM2 has a variety of tumor progressive functions in OSCC cells.
2
Sturgill, Eric M., and Monica L. Guzman. "Cytokine Induced Nuclear Localization Of Pyruvate Kinase M2 In Acute Myeloid Leukemia." Blood 122, no. 21 (November 15, 2013): 5406. http://dx.doi.org/10.1182/blood.v122.21.5406.5406.
Full textAbstract:
Abstract A common characteristic among nearly all cancers, including leukemia, is the cell’s metabolic proclivity for glycolysis over the more energy efficient process of oxidative phosphorylation (OXPHOS) in the presence of oxygen. This altered state of aerobic glycolysis was observed in tumor cells by Otto Warburg over fifty years ago (Warburg, 1956) and continues to be intensely investigated in hopes of ultimately exploiting this “Warburg effect” in the treatment of cancer (Vander Heiden et al. 2009). Recent studies have revealed that the M2 isoform of the enzyme pyruvate kinase (PKM2) plays a critical role in the maintenance of aerobic glycolysis in tumor cells and is important for their growth and development (Christofk et al. 2008). Pyruvate kinase produces pyruvate and one molecule of adenosine 5’-triphosphate (ATP) in the rate-limiting step of glycolysis. Pyruvate kinase coded for by PKM has two splice isoforms, the constitutively active PKM1 that exists only as a tetramer and PKM2 that can shift between a more active tetramer and less active dimers or monomers. The dynamic enzymatic activity of PKM2 is key to its preferential expression in tumor cells. By utilizing the less active form of PKM2, tumor cells can limit the levels of pyruvate available for OXPHOS and instead shunt glycolytic carbons towards anabolic processes. However, recent studies have revealed novel activities of PKM2 outside the realm of energy metabolism that also contribute to tumor formation, maintenance, and growth. The less active PKM2 dimer, whose structure is favored upon phosphorylation at Tyr105 (Hitosugi et al. 2009), can also translocate to the nucleus and act as a transcription factor for cell cycle associated genes like MYC and CCND1 upon stimulation with epidermal growth factor in certain cancer cell lines (Gao et al. 2012). Acute myeloid leukemia (AML) is a malignancy of hematopoietic progenitor cells characterized by the extraordinarily rapid growth of abnormal myeloid cells, making the proliferative influences of PKM2 an intriguing target for therapy. We have found that PKM2 is abundantly expressed in AML cell lines and primary AML patient samples and that low basal levels of PKM2 can be detected in their nuclei. Interestingly, stimulation with various cytokines such as IL-6 or GM-CSF can induce the nuclear translocation of PKM2 and association with histone H3 in these cells and concomitant treatment with PKM2 activating compounds that have been shown to promote its tetrameric structure and suppress tumor growth (Anastasiou et al. 2012) can inhibit this effect. These data show that the role of PKM2 in regulating transcription in addition to its metabolic activity may be important for the proliferation and maintenance of hematopoietic malignancies. Using fluorescence-activated cell sorting to isolate specific sub-populations of primary AML patient cells and elucidating PKM2’s interaction with protein kinases involved in known signaling pathways like JAK/STAT, ERK1/2, and FLT3, we show that the proliferative influences of PKM2 function and activity differ between AML cell phenotypes. For example, cells from AML patient samples sorted based on high or low levels of reactive oxygen species (ROS) differ in relative phosphorylation of PKM2 at Tyr105. These data, along with reports that the PKM2 dimer specifically plays a role in tumor cell antioxidant response (Anastasiou, et al. 2011) suggests that PKM2 may contribute to the maintenance of phenotypically ROS-low leukemia stem cells that are thought to contribute to patient relapse after achieving remission (Hope et al. 2004). Our data suggests that the broad cellular functions of PKM2 employed by AML cells and its direct influence on tumor growth and survival make it a promising potential target for therapy. Disclosures: No relevant conflicts of interest to declare.
3
Nayak, Manasa, Nirav Dhanesha, Manish Jain, and Anil Chauhan. "Manipulating Metabolic Plasticity By Targeting Pyruvate Kinase M2 in Platelets Inhibits Arterial Thrombosis." Blood 132, Supplement 1 (November 29, 2018): 868. http://dx.doi.org/10.1182/blood-2018-99-112704.
Full textAbstract:
Abstract Background: Most of the cellular responses initiated upon platelet activation are energy consuming. Like normal cells, resting platelets rely primarily on oxidative phosphorylation (OXPHOS) to generate ATP, whereas activated platelets exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen, a phenomenon referred to as the Warburg effect in tumor cells) suggesting that metabolic plasticity exists in activated platelets. Although aerobic glycolysis yields less total ATP when compared to OXPHOS, the rate of ATP generation is faster in aerobic glycolysis compared to OXPHOS, which is well suited for high-energy demands during platelet activation. Pyruvate kinases (PKs) catalyzes the final step of glycolysis, the formation of pyruvate and ATP from phosphoenolpyruvate and ADP. Four PK isoforms exist in mammals: L and R isoforms are expressed in the liver and red blood cells; the M1 isoform is expressed in most adult tissues that have high catabolic demands including muscle and brain; M2 is expressed in cells including activated platelets and leukocytes. While PKM1 and tetrameric PKM2 favor ATP production from OXPHOS through the TCA cycle, dimeric PKM2 drives aerobic glycolysis. Objective: We tested an innovative concept that by manipulating the energy demand of activated platelets (metabolic plasticity), by targeting PKM2, will inhibit platelet function and thrombosis. Methods: Using a specific inhibitor of PKM2 (inhibits PKM2 dimerization and stabilizes tetramers) and standardized platelet in vitro assays, we determined the mechanistic role of PKM2 in modulating platelet function in human and mice. To provide definitive evidence, we generated a megakaryocyte or platelet-specific PKM2-/- mouse (PKM2fl/flPF4Cre). Lactate assay was performed in WT and PKM2 null platelets. Susceptibility to thrombosis was evaluated in vitro (microfluidics flow chamber) and in vivo (FeCl3-induced carotid artery thrombosis and laser injury models) by utilizing intravital microscopy. Results: We found that PKM2 is relatively highly expressed compared to PKM1 in human and murine platelets. Transmission electron microscopy (immunogold staining) revealed that PKM2 is found in the cytoplasm and a- granule in resting platelets, whereas most of PKM2 translocated to cytoplasm upon activation. Human and mouse platelets pretreated with PKM2 inhibitor exhibited decreased platelet aggregation to sub-optimal doses of collagen and convulxin but not to thrombin. In microfluidics flow chamber assay, human and whole mouse blood pretreated with PKM2 inhibitor formed small thrombi when perfused over collagen for 5 min at an arterial shear rate of 1500s-1 (P<0.05 vs. vehicle control). Platelets from PKM2fl/flPF4Cre mice exhibited decreased platelet aggregation to sub-optimal doses of collagen and convulxin, but not to thrombin, compared to PKM2fl/fl mice concomitant with decrease lactate production. In microfluidics flow chamber assay, whole blood from PKM2fl/flPF4Cre mice formed smaller thrombi when perfused over collagen for 5 min at an arterial shear rate of 1500s-1, compared to PKM2fl/fl mice. PKM2fl/flPF4Cre mice were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models (P<0.05 vs. vehicle control, N=10 mice/group), without altering hemostasis. PKM2 regulates the phosphorylation signal transducer and activator of transcription 3 (STAT3) and p-STAT3 act as a protein scaffold that facilitates the catalytic process of activating PLCg by kinase Syk in response to low-doses of collagen and CRP, but not TRAP or ADP in human and murine platelets. Interestingly, we found that PKM2 and STAT3 colocalized in the convulixn- stimulated control platelets and less phosphorylation of STAT-3 was observed in activated PKM2 null platelets (P<0.05 vs. WT), suggesting a non-glycolytic role of the PKM2 in regulating collagen signaling. Conclusions: Our results suggest that dimeric PKM2 regulates platelet function and arterial thrombosis most likely via GPVI signaling pathway. We suggest that manipulating metabolic plasticity by targeting dimeric PKM2 may be explored as a novel strategy to inhibit platelet function and arterial thrombosis. Disclosures No relevant conflicts of interest to declare.
4
Xia, Li, Xin-Ran Wang, Ran Wei, Jin-Song Yan, Guo-Qiang Chen, and Ying Lu. "Sumoylation of Pyruvate Kinase M2 Inhibits Myeloid Differentiation in Hematopoietic Cells." Blood 132, Supplement 1 (November 29, 2018): 3919. http://dx.doi.org/10.1182/blood-2018-99-117899.
Full textAbstract:
Abstract The pyruvate kinase (PK) is a rate-limiting glycolytic enzyme catalyzing the dephosphorylation of phosphoenolpyruvate to pyruvate. M2 form of PK (PKM2) is expressed during embryogenesis and is the predominant form in tumors of different types. In contrast to the essential role of PKM2 in solid tumors, much less is known about the effects of PKM2 in hematopoietic cells and the development of leukemia. Here we found that PKM2 is modified by small ubiquitin-like modifier 1(SUMO1), which can be reduced by a SUMO1-specific protease SENP1 in hematopoietic cells. SUMOylation induced nuclear localization and conformation change from tetramer to dimer of PKM2. Importantly, SUMOylation of PKM2 is prevalent in a variety of leukemic cell lines as well as primary samples from patients with hematologic malignancies. In consistency, predominant nuclear localization and dimeric forms of PKM2 in leukemic cells were observed. Using in vitro SUMOylation reaction-coupled liquid chromatography-mass spectrometry/mass spectrometry (LC-MS/MS), we identified K270 lysine residue of PKM2 as the SUMOylation target. Replacement of endogenous PKM2 with mutant PKM2K270 showed a significant shift of PKM2 from tetramer to dimer. To investigate the potential leukemogenic effect of PKM2 SUMOylation, murine hematopoietic progenitor 32D clone 3 (32Dcl3) transfectants expressing wild type(WT) or mutant PKM2K270 were generated and G-CSF-induced differentiation was evaluated by morphology appearance and expression of myeloid associated surface markers CD11b and Gr-1. The results showed that expression of WT PKM2 but not mutant PKM2K270 significantly blocked myeloid differentiation. Further investigations revealed that SUMO1 modification of PKM2 at K270 is essential in mediating the interaction between PKM2 and Runt-related transcription factor 1(RUNX1), a master transcriptional factor implicated in the differentiation of hematopoietic cells. This interaction led to a downregulation of RUNX1 during G-CSF-induced myeloid differentiation of 32D cells, which could be abrogated by expression of mutant PKM2K270. Collectively, these data indicated that SUMOylated PKM2 blocks myeloid differentiation through suppressing RUNX1. These findings reveal a novel nonmetabolic function of PKM2 in modulating myeloid differentiation and highlight the critical role of SUMOylation in leukemogenesis. Disclosures No relevant conflicts of interest to declare.
5
Su, Yan, Sujuan Guo, Chunyan Liu, Na Li, Shuang Zhang, Yubin Ding, Xuemei Chen, et al. "Endometrial pyruvate kinase M2 is essential for decidualization during early pregnancy." Journal of Endocrinology 245, no. 3 (June 2020): 357–68. http://dx.doi.org/10.1530/joe-19-0553.
Full textAbstract:
Embryo implantation is essential for normal pregnancy. Decidualization is known to facilitate embryo implantation and maintain pregnancy. Uterine stromal cells undergo transformation into decidual cells after embryo attachment to the endometrium. Pyruvate kinase M2 (PKM2) is a rate limiting enzyme in the glycolysis process which catalyzes phosphoenolpyruvic acid into pyruvate. However, little is known regarding the role of PKM2 during endometrial decidualization. In this study, PKM2 was found to be mainly located in the uterine glandular epithelium and luminal epithelium on day 1 and day 4 of pregnancy and strongly expressed in the decidual zone after embryo implantation. PKM2 was dramatically increased with the onset of decidualization. Upon further exploration, PKM2 was found to be more highly expressed at the implantation sites than at the inter-implantation sites on days 5 to 7 of pregnancy. PKM2 expression was also significantly increased after artificial decidualization both in vivo and in vitro. After PKM2 expression was knocked down by siRNA, the number of embryo implantation sites in mice on day 7 of pregnancy was significantly reduced, and the decidualization markers BMP2 and Hoxa10 were also obviously downregulated in vivo and in vitro. Downregulated PKM2 could also compromise cell proliferation in primary endometrial stromal cells and in Ishikawa cells. The migration rate of Ishikawa cells was also obviously suppressed by si-PKM2 according to the wound healing assay. In conclusion, PKM2 might play an important role in decidualization during early pregnancy, and cell proliferation might be one pathway for PKM2 regulated decidualization.
6
Esen, I., Y. Van Sleen, P. Heeringa, A. Boots, and E. Brouwer. "AB0471 ELEVATED EXPRESSION OF PYRUVATE KINASE M2 IN GIANT CELL ARTERITIS." Annals of the Rheumatic Diseases 79, Suppl 1 (June 2020): 1534.1–1534. http://dx.doi.org/10.1136/annrheumdis-2020-eular.1699.
Full textAbstract:
Background:Giant Cell Arteritis (GCA) is an inflammatory disease of large and medium vessels. In GCA, expression of interleukin-6 (IL-6), a systemic marker of inflammation, is elevated and it has been shown that treatment with IL-6 receptor blockade (Tocilizumab) is beneficial for GCA patients.1To investigate the role of the IL-6 signaling pathway in GCA pathogenesis in more depth, we focused on the metabolic enzyme Pyruvate Kinase M2 (PKM2). PKM2 may exist as a tetramer, a dimer and/or a monomer in the cell. Tetrameric PKM2 acts as a glycolytic enzyme and catalyzes the last steps of glycolysis by converting phosphoenolpyruvate (PEP) to pyruvate and ATP. On the other hand, dimeric PKM2 translocates to the nucleus and mediates gene regulation via its non-canonical protein kinase activity. Dimeric PKM2 regulates hypoxia, IL-1β expression and, phosphorylates signal transducer and activator of transcription 3 (STAT3) which functions downstream of the IL-6 signaling pathway.2Objectives:To investigate the role of PKM2 in GCA diagnosis and pathogenesis.Methods:Immunohistochemical staining for PKM2 was performed on inflamed (n=8) and non-inflamed (n=4) temporal artery biopsies (TAB) from GCA patients and on TAB from non-GCA (n=9) patients. To detect soluble, dimeric PKM2 in plasma commercially available dimeric PKM2 specific ELISA kit was used. To determine the modulation of dimeric PKM2 by treatment, samples of GCA patients at baseline (n=44), at 6 weeks (n=32) and at 1 year (n=31) after treatment were compared to samples from age- and sex-matched healthy controls (HC, n=45) As a positive control, samples from melanoma patients (n =8) were used. To investigate the role of dimeric PKM2 in the pathogenesis of GCA, we correlated PKM2 plasma levels with markers of inflammation (CRP, IL-6) and markers of angiogenesis (Angpt2, VEGF, YKL40). Statistical analysis included the Mann-Whitney U test for comparing different groups while the Wilcoxon rank test was used for paired samples. Correlations were assessed by Spearman’s rank correlation coefficient.Results:High expression of PKM2 was found in inflamed and non-inflamed TABs of GCA patients, while in non-GCA TABs PKM2 was sparsely expressed. Circulating levels of dimeric PKM2 were found elevated in melanoma and in GCA patients at baseline/active disease compared to those in healthy controls. Analysis of 6 weeks and 1 year follow up plasma samples showed that plasma levels of dimeric PKM2 significantly decreased upon treatment. Dimeric PKM2 weakly correlated with CRP at baseline (r=0.399, p=0.048) but not with angiogenesis markers.Conclusion:Dimeric PKM2 plasma levels were found elevated in GCA patients at baseline. PKM2 plasma levels were down modulated by treatment. PKM2 plasma levels weakly correlated with inflammation marker CRP. The data suggest that PKM2 as a marker of glycolysis may have relevance in GCA at diagnosis and for monitoring disease activity. Future studies should aim to validate PKM2 in an independent cohort. Additional studies are needed to determine the molecular mechanism underlying the increase in elevated dimeric PKM2 levels and how this may contribute to IL-6 signaling.References:[1]Samson M, Corbera-Bellalta M, Audia S, Planas-Rigol E, Martin L, Cid MC, Bonnotte B. Recent advances in our understanding of giant cell arteritis pathogenesis. Autoimmunity reviews. 2017;16(8):833-44.[2]Alquraishi M, Puckett DL, Alani DS, Humidat AS, Frankel VD, Donohoe DR, Whelan J, Bettaieb A. Pyruvate kinase M2: A simple molecule with complex functions. Free Radical Biology and Medicine.2019;143:176-192.Acknowledgments:This project received funding from the EU Horizon 2020 research and innovation program under the Marie Sklodowska-Curie grant agreement 754425.Disclosure of Interests:Idil Esen: None declared, Yannick van Sleen: None declared, Peter Heeringa: None declared, Annemieke Boots Consultant of: Grünenthal Gmbh until 2017, Elisabeth Brouwer Consultant of: Roche (consultancy fee 2017 and 2018 paid to the UMCG), Speakers bureau: Roche (2017 and 2018 paid to the UMCG)
7
Goldberg, Michael S., and Phillip A. Sharp. "Pyruvate kinase M2-specific siRNA induces apoptosis and tumor regression." Journal of Experimental Medicine 209, no. 2 (January 23, 2012): 217–24. http://dx.doi.org/10.1084/jem.20111487.
Full textAbstract:
The development of cancer-specific therapeutics has been limited because most healthy cells and cancer cells depend on common pathways. Pyruvate kinase (PK) exists in M1 (PKM1) and M2 (PKM2) isoforms. PKM2, whose expression in cancer cells results in aerobic glycolysis and is suggested to bestow a selective growth advantage, is a promising target. Because many oncogenes impart a common alteration in cell metabolism, inhibition of the M2 isoform might be of broad applicability. We show that several small interfering (si) RNAs designed to target mismatches between the M2 and M1 isoforms confer specific knockdown of the former, resulting in decreased viability and increased apoptosis in multiple cancer cell lines but less so in normal fibroblasts or endothelial cells. In vivo delivery of siPKM2 additionally causes substantial tumor regression of established xenografts. Our results suggest that the inherent nucleotide-level specificity of siRNA can be harnessed to develop therapeutics that target isoform-specific exons in genes exhibiting differential splicing patterns in various cell types.
8
Sharma, Pankaj. "Molecular docking analysis of pyruvate kinase M2 with a potential inhibitor from the ZINC database." Bioinformation 17, no. 1 (January 31, 2021): 139–46. http://dx.doi.org/10.6026/97320630017139.
Full textAbstract:
The pyruvate kinase M2 isoform (PKM2) is linked with cancer. Therefore, it is of interest to document the molecular docking analysis of Pyruvate Kinase M2 (PDB ID: 4G1N) with potential activators from the ZINC database. Thus, we document the optimal molecular docking features of a compound having ID ZINC000034285235 with PKM2 for further consideration.
9
Choi, Hae-Seul, Chang-Zhu Pei, Jun-Hyeok Park, Soo-Yeon Kim, Seung-Yeon Song, Gyeong-Jin Shin, and Kwang-Hyun Baek. "Protein Stability of Pyruvate Kinase Isozyme M2 Is Mediated by HAUSP." Cancers 12, no. 6 (June 12, 2020): 1548. http://dx.doi.org/10.3390/cancers12061548.
Full textAbstract:
The ubiquitin–proteasome system (UPS) is responsible for proteasomal degradation, regulating the half-life of the protein. Deubiquitinating enzymes (DUBs) are components of the UPS and inhibit degradation by removing ubiquitins from protein substrates. Herpesvirus-associated ubiquitin-specific protease (HAUSP) is one such deubiquitinating enzyme and has been closely associated with tumor development. In a previous study, we isolated putative HAUSP binding substrates by two-dimensional electrophoresis (2-DE) and identified them by matrix-assisted laser desorption-ionization time-of-flight mass spectrometry (MALDI-TOF/MS) analysis. The analysis showed that pyruvate kinase isoenzyme M2 (PKM2) was likely to be one of the substrates for HAUSP. Further study revealed that PKM2 binds to HAUSP, confirming the interaction between these proteins, and that PKM2 possesses the putative HAUSP binding motif, E or P/AXXS. Therefore, we generated mutant forms of PKM2 S57A, S97A, and S346A, and found that S57A had less binding affinity. In a previous study, we demonstrated that PKM2 is regulated by the UPS, and that HAUSP- as a DUB-acted on PKM2, thus siRNA for HAUSP increases PKM2 ubiquitination. Our present study newly highlights the direct interaction between HAUSP and PKM2.
10
Rathod, Bhagyashri, Shivam Chak, Sagarkumar Patel, and Amit Shard. "Tumor pyruvate kinase M2 modulators: a comprehensive account of activators and inhibitors as anticancer agents." RSC Medicinal Chemistry 12, no. 7 (2021): 1121–41. http://dx.doi.org/10.1039/d1md00045d.
Full text
11
Wang, Guiping, Yingying Zhong, Jiecong Liang, Zhibin Li, and Yun Ye. "Upregulated expression of pyruvate kinase M2 mRNA predicts poor prognosis in lung adenocarcinoma." PeerJ 8 (February 20, 2020): e8625. http://dx.doi.org/10.7717/peerj.8625.
Full textAbstract:
Background Pyruvate kinase M2 (PKM2) is critical regulator contributing to Warburg effect. However, the expression pattern and prognostic value of PKM2 remain unknown in lung adenocarcinoma (LUAD). The aim of this study is to clarify the prognostic value of PKM2 via intergrated bioinformatics analysis. Methods Firstly, mRNA expression levels of PKM2 in LUAD were systematically analyzed using the ONCOMINE and TCGA databases. Then, the association between PKM2 expression and clinical parameters was investigated by UALCAN. The Kaplan–Meier Plotter was used to assess the prognostic significance of PKM2. Finally, the relationship between PKM2 expression and its genetic and epigenetic changes was evaluated with MEXPRESS and MethHC database. Results Pooled analysis showed that PKM2 is frequently upregulated expression in LUAD. Subsequently, PKM2 expression was identified to be positively associated with tumor stage and lymph node metastasis and also strongly correlated with worse OS (P = 2.80e−14), PPS (P = 0.022), FP (P = 1.30e−6) and RFS (P = 3.41e−8). Importantly, our results demonstrated that over-expressed PKM2 is associated with PKM2 hypomethylation and copy number variations (CNVs). Conclusion This study confirms that over-expressed PKM2 in LUAD is associated with poor prognosis, suggesting that PKM2 might act as a promising prognostic biomarker and novel therapeutic target for LUAD.
12
Nayak, Manasa K., Madankumar Ghatge, Nirav Dhanesha, Gagan D. Flora, Manish Jain, Omar Rodriguez, Kathleen Markan, Mathhhew Potthoff, Steven R. Lentz, and Anil K. Chauhan. "Targeting Metabolic Enzyme Pyruvate Kinase M2: A Novel Strategy to Inhibit Platelet Function and Arterial Thrombosis." Blood 134, Supplement_1 (November 13, 2019): 1056. http://dx.doi.org/10.1182/blood-2019-129027.
Full textAbstract:
Background: The cellular responses initiated upon platelet activation are energy consuming. Activated platelets, in comparison to their resting state, exhibit a high level of aerobic glycolysis (conversion of glucose to lactate in the presence of oxygen) relative to oxidative phosphorylation (OXPHOS), suggesting that metabolic plasticity exists in platelets. Although aerobic glycolysis yields less total ATP when compared to OXPHOS, the rate of ATP generation is faster in aerobic glycolysis compared to OXPHOS, which we hypothesize is well suited for high-energy requirement during platelet activation. The glycolytic enzyme pyruvate kinases (PKs) catalyzes the final step of glycolysis and contributes to net ATP production. Four PK isoforms (L, R, M1 and M2) exist in mammals: L and R isoforms are expressed in the liver and red blood cells; the M1 isoform is expressed in most adult tissues that have high catabolic demands including muscle and brain; M2 is expressed in cells including activated platelets and leukocytes. Unlike other isoforms of PK that function only as tetramers, PKM2 can exist in either a tetrameric state or a dimeric state. PKM2 is allosterically regulated by the upstream metabolite fructose-1, 6 biphosphate. While PKM1 and tetrameric PKM2 favor ATP production from OXPHOS through the TCA cycle, dimeric PKM2 drives aerobic glycolysis. The glycolytic and non-glycolytic functions of PKM2 in platelets have not investigated yet. Objective: We tested an innovative concept that whether targeting metabolic enzyme PKM2 will inhibit platelet function and arterial thrombosis. Methods: Using a specific inhibitor of PKM2 (that prevents PKM2 dimerization and stabilizes tetramers) and a range of standardized platelet in vitro assays, we determined the mechanistic role of PKM2 in modulating platelet function in human and mice. To provide definitive evidence, we generated a megakaryocyte or platelet-specific PKM2-/- mouse (PKM2fl/flPF4Cre). Susceptibility to thrombosis was evaluated in vitro (microfluidics flow chamber) and in vivo (FeCl3-induced carotid and laser-injury induced mesenteric artery thrombosis models) by utilizing intravital microscopy. Susceptibility to hemostasis was evaluated in tail bleeding assay. Results: Human and mouse platelets pretreated with PKM2 inhibitor significantly decreased platelet aggregation to sub-optimal doses of collagen, convulxin, thrombin, and ADP. Consistent with this, inhibiting PKM2 dimerization reduced αIIbβ3 activation, alpha and dense granule secretion, clot retraction that was concomitant with decreased glucose uptake. Furthermore, treatment with PKM2 inhibitor reduced Akt and GSK3β phosphorylation, that are predominantly involved in PI3K/Akt signaling, suggesting a non-glycolytic role of the PKM2 in regulating platelet function. In microfluidics flow chamber assay, human and whole mouse blood pretreated with PKM2 inhibitor formed small thrombi when perfused over collagen for 5 minutes at an arterial shear rate of 1500s-1 (P<0.05 vs. vehicle). In agreement with PKM2 inhibitor studies, platelets from PKM2fl/flPF4Cre mice exhibited decreased agonist-induced platelet aggregation, which was in agreement with decreased alpha and dense granule secretion, αIIbβ3 activation, clot retraction, lactate production, and Akt and GSK3β phosphorylation (P<0.05 vs. PKM2fl/fl littermate controls). Wild-type mice-treated with PKM2 inhibitor and/or PKM2fl/flPF4Cre were less susceptible to thrombosis in the FeCl3-induced carotid and laser injury-induced mesenteric artery thrombosis models. Lack of effect on tail bleeding time suggested normal hemostasis in PKM2fl/flPF4Cre mice and PKM2 inhibitor-treated wild-type mice. No sex-based differences were observed. Currently, we are performing platelet metabolomics to determine the effect of targeting PKM2 on metabolic pathways. Conclusions: Our results suggest that manipulating metabolic plasticity by targeting dimeric PKM2 may be explored as a novel strategy to inhibit platelet function and arterial thrombosis. Disclosures Lentz: Novo Nordisk Inc.: Consultancy, Honoraria, Research Funding.
13
Nandi, Suparno, Mortezaali Razzaghi, Dhiraj Srivastava, and Mishtu Dey. "Structural basis for allosteric regulation of pyruvate kinase M2 by phosphorylation and acetylation." Journal of Biological Chemistry 295, no. 51 (September 28, 2020): 17425–40. http://dx.doi.org/10.1074/jbc.ra120.015800.
Full textAbstract:
Pyruvate kinase muscle isoform 2 (PKM2) is a key glycolytic enzyme and transcriptional coactivator and is critical for tumor metabolism. In cancer cells, native tetrameric PKM2 is phosphorylated or acetylated, which initiates a switch to a dimeric/monomeric form that translocates into the nucleus, causing oncogene transcription. However, it is not known how these post-translational modifications (PTMs) disrupt the oligomeric state of PKM2. We explored this question via crystallographic and biophysical analyses of PKM2 mutants containing residues that mimic phosphorylation and acetylation. We find that the PTMs elicit major structural reorganization of the fructose 1,6-bisphosphate (FBP), an allosteric activator, binding site, impacting the interaction with FBP and causing a disruption in oligomerization. To gain insight into how these modifications might cause unique outcomes in cancer cells, we examined the impact of increasing the intracellular pH (pHi) from ∼7.1 (in normal cells) to ∼7.5 (in cancer cells). Biochemical studies of WT PKM2 (wtPKM2) and the two mimetic variants demonstrated that the activity decreases as the pH is increased from 7.0 to 8.0, and wtPKM2 is optimally active and amenable to FBP-mediated allosteric regulation at pHi 7.5. However, the PTM mimetics exist as a mixture of tetramer and dimer, indicating that physiologically dimeric fraction is important and might be necessary for the modified PKM2 to translocate into the nucleus. Thus, our findings provide insight into how PTMs and pH regulate PKM2 and offer a broader understanding of its intricate allosteric regulation mechanism by phosphorylation or acetylation.
14
Kim, Hyunju, Seong Ho Kim, Dohyeon Hwang, Jinsu An, Hak Suk Chung, Eun Gyeong Yang, and So Yeon Kim. "Extracellular pyruvate kinase M2 facilitates cell migration by upregulating claudin-1 expression in colon cancer cells." Biochemistry and Cell Biology 98, no. 2 (April 2020): 219–26. http://dx.doi.org/10.1139/bcb-2019-0139.
Full textAbstract:
Extensive studies have been reported the non-canonical functions of pyruvate kinase M2 (PKM2) as a kinase, transcriptional regulator, and even cell-to-cell communicator, emphasizing its importance in various signaling pathways. However, the role of secreted PKM2 in cancer progression and its signaling pathway is yet to be elucidated. In this study, we found that extracellular PKM2 enhanced the migration of low-metastatic, benign colon cancer cells by upregulating claudin-1 expression and internalizing it to the cytoplasm and nucleus. Knock-down of claudin-1 significantly reduced extracellular PKM2-induced cell migration. Inhibition of either protein kinase C (PKC) or epidermal growth factor receptor (EGFR) resulted in a reduction of extracellular PKM2-mediated claudin-1 expression, suggesting EGFR–PKC–claudin-1 as a signaling pathway in the extracellular PKM2-mediated tumorigenesis of colon cancer cells.
15
Kumar, Amit, Priya Gupta, Minakshi Rana, Tulika Chandra, Madhu Dikshit, and Manoj Kumar Barthwal. "Role of pyruvate kinase M2 in oxidized LDL-induced macrophage foam cell formation and inflammation." Journal of Lipid Research 61, no. 3 (January 27, 2020): 351–64. http://dx.doi.org/10.1194/jlr.ra119000382.
Full textAbstract:
Pyruvate kinase M2 (PKM2) links metabolic and inflammatory dysfunction in atherosclerotic coronary artery disease; however, its role in oxidized LDL (Ox-LDL)-induced macrophage foam cell formation and inflammation is unknown and therefore was studied. In recombinant mouse granulocyte-macrophage colony-stimulating factor-differentiated murine bone marrow-derived macrophages, early (1–6 h) Ox-LDL treatment induced PKM2 tyrosine 105 phosphorylation and promotes its nuclear localization. PKM2 regulates aerobic glycolysis and inflammation because PKM2 shRNA or Shikonin abrogated Ox-LDL-induced hypoxia-inducible factor-1α target genes lactate dehydrogenase, glucose transporter member 1, interleukin 1β (IL-1β) mRNA expression, lactate, and secretory IL-1β production. PKM2 inhibition significantly increased Ox-LDL-induced ABCA1 and ABCG1 protein expression and NBD-cholesterol efflux to apoA1 and HDL. PKM2 shRNA significantly inhibited Ox-LDL-induced CD36, FASN protein expression, DiI-Ox-LDL binding and uptake, and cellular total cholesterol, free cholesterol, and cholesteryl ester content. Therefore, PKM2 regulates lipid uptake and efflux. DASA-58, a PKM2 activator, downregulated LXR-α, ABCA1, and ABCG1, and augmented FASN and CD36 protein expression. Peritoneal macrophages showed similar results. Ox-LDL induced PKM2- SREBP-1 interaction and FASN expression in a PKM2-dependent manner. Therefore, this study suggests a role for PKM2 in Ox-LDL-induced aerobic glycolysis, inflammation, and macrophage foam cell formation.
16
Dey, Son, Kundu, Kim, Lee, Yoon, Yoon, Lee, Nam, and Kim. "Knockdown of Pyruvate Kinase M2 Inhibits Cell Proliferation, Metabolism, and Migration in Renal Cell Carcinoma." International Journal of Molecular Sciences 20, no. 22 (November 10, 2019): 5622. http://dx.doi.org/10.3390/ijms20225622.
Full textAbstract:
Emerging evidence indicates that the activity of pyruvate kinase M2 (PKM2) isoform is crucial for the survival of tumor cells. However, the molecular mechanism underlying the function of PKM2 in renal cancer is undetermined. Here, we reveal the overexpression of PKM2 in the proximal tubule of renal tumor tissues from 70 cases of patients with renal carcinoma. The functional role of PKM2 in human renal cancer cells following small-interfering RNA-mediated PKM2 knockdown, which retarded 786-O cell growth was examined. Targeting PKM2 affected the protein kinase B (AKT)/mechanistic target of the rapamycin 1 (mTOR) pathway, and downregulated the expression of glycolytic enzymes, including lactate dehydrogenase A and glucose transporter-1, and other downstream signaling key proteins. PKM2 knockdown changed glycolytic metabolism, mitochondrial function, adenosine triphosphate (ATP) level, and intracellular metabolite formation and significantly reduced 786-O cell migration and invasion. Acridine orange and monodansylcadaverine staining, immunocytochemistry, and immunoblotting analyses revealed the induction of autophagy in renal cancer cells following PKM2 knockdown. This is the first study to indicate PKM2/AKT/mTOR as an important regulatory axis mediating the changes in the metabolism of renal cancer cells.
17
Chen, Kuan-Chung, Kuen-Bao Chen, Hsin-Yi Chen, and Calvin Yu-Chian Chen. "In SilicoInvestigation of Potential Pyruvate Kinase M2 Regulators from Traditional Chinese Medicine against Cancers." BioMed Research International 2014 (2014): 1–14. http://dx.doi.org/10.1155/2014/189495.
Full textAbstract:
A recent research in cancer research demonstrates that tumor-specific pyruvate kinase M2 (PKM2) plays an important role in chromosome segregation and mitosis progression of tumor cells. To improve the drug development of TCM compounds, we aim to identify potent TCM compounds as lead compounds of PKM2 regulators. PONDR-Fit protocol was utilized to predict the disordered disposition in the binding domain of PKM2 protein before virtual screening as the disordered structure in the protein may cause the side effect and downregulation of the possibility of ligand to bind with target protein. MD simulation was performed to validate the stability of interactions between PKM2 proteins and each ligand after virtual screening. The top TCM compounds, saussureamine C and precatorine, extracted fromLycium chinenseMill. andAbrus precatoriusL., respectively, have higher binding affinities with target protein in docking simulation than control. They have stable H-bonds with residues A:Lys311 and some other residues in both chains of PKM2 protein. Hence, we propose the TCM compounds, saussureamine C and precatorine, as potential candidates as lead compounds for further study in drug development process with the PKM2 protein against cancer.
18
Yang, Peng, Guo-Bin Ding, Wen Liu, Rong Fu, Amin Sajid, and Zhuoyu Li. "Tannic acid directly targets pyruvate kinase isoenzyme M2 to attenuate colon cancer cell proliferation." Food & Function 9, no. 11 (2018): 5547–59. http://dx.doi.org/10.1039/c8fo01161c.
Full textAbstract:
Tannic acid, which ubiquitously exists in grapes and green tea, binds to K433 to trigger dissociation of PKM2 tetramers and further block the metabolic activity of PKM2 to suppress colorectal cancer cell proliferation.
19
Dai, Jinlu, June Escara-Wilke, Jill M. Keller, Younghun Jung, Russell S. Taichman, Kenneth J. Pienta, and Evan T. Keller. "Primary prostate cancer educates bone stroma through exosomal pyruvate kinase M2 to promote bone metastasis." Journal of Experimental Medicine 216, no. 12 (September 23, 2019): 2883–99. http://dx.doi.org/10.1084/jem.20190158.
Full textAbstract:
Prostate cancer (PCa) metastasizes selectively to bone through unknown mechanisms. In the current study, we identified exosome-mediated transfer of pyruvate kinase M2 (PKM2) from PCa cells into bone marrow stromal cells (BMSCs) as a novel mechanism through which primary tumor-derived exosomes promote premetastatic niche formation. We found that PKM2 up-regulates BMSC CXCL12 production in a HIF-1α-dependent fashion, which subsequently enhances PCa seeding and growth in the bone marrow. Furthermore, serum-derived exosomes from patients with either primary PCa or PCa metastasis, as opposed to healthy men, reveal that increased exosome PKM2 expression is associated with metastasis, suggesting clinical relevance of exosome PKM2 in PCa. Targeting the exosome-induced CXCL12 axis diminished exosome-mediated bone metastasis. In summary, primary PCa cells educate the bone marrow to create a premetastatic niche through primary PCa exosome-mediated transfer of PKM2 into BMSCs and subsequent up-regulation of CXCL12. This novel mechanism indicates the potential for exosome PKM2 as a biomarker and suggests therapeutic targets for PCa bone metastasis.
20
Tsai, Kary Y. F., Benton Tullis, Juan Mejia, Paul R. Reynolds, and Juan A. Arroyo. "Regulation of trophoblast cell invasion by Pyruvate Kinase isozyme M2 (PKM2)." Placenta 103 (January 2021): 24–32. http://dx.doi.org/10.1016/j.placenta.2020.10.019.
Full text
21
Li, Zhichao, Hanqing Li, Yangxu Lu, Peng Yang, and Zhuoyu Li. "Berberine Inhibited the Proliferation of Cancer Cells by Suppressing the Activity of Tumor Pyruvate Kinase M2." Natural Product Communications 12, no. 9 (September 2017): 1934578X1701200. http://dx.doi.org/10.1177/1934578x1701200909.
Full textAbstract:
Berberine, an isoquinoline alkaloid extracted from coptis, exerts anti-proliferation and anticancer properties. Pyruvate kinase M2 (PKM2) is a key enzyme of aerobic glycolysis and considered as the potential anticancer target. However, the inhibition effects and interaction action between Berberine and PKM2 is not well known. In this study, berberine showed antitumor activity of HCT-116 and HeLa cells with the suppression of cell proliferation. Moreover, berberine inhibited the enzyme activity of PKM2 in cancer cells, but had no impact on PKM2 expression. Further research showed that the interaction between berberine and PKM2 was dynamic fluorescence quenching and the main intermolecular force was hydrogen bonding. These findings revealed that berberine may serve as a therapeutic drug for cancer chemotherapy.
22
Lee, Seoung-Ae, Charles Ho, Madison Troxler, Chin-Yo Lin, and Sang-Hyuk Chung. "Non-Metabolic Functions of PKM2 Contribute to Cervical Cancer Cell Proliferation Induced by the HPV16 E7 Oncoprotein." Viruses 13, no. 3 (March 8, 2021): 433. http://dx.doi.org/10.3390/v13030433.
Full textAbstract:
Pyruvate kinase M2 (PKM2) mainly catalyzes glycolysis, but it also exerts non-glycolytic functions in several cancers. While it has been shown to interact with the human papillomavirus 16 (HPV16) E7 oncoprotein, the functional significance of PKM2 in HPV-associated cervical cancer has been elusive. Here, we show that HPV16 E7 increased the expression of PKM2 in cervical cancer cells. TCGA data analyses revealed a higher level of PKM2 in HPV+ than HPV− cervical cancers and a worse prognosis for patients with high PKM2 expression. Functionally, we demonstrate that shRNA-mediated PKM2 knockdown decreased the proliferation of HPV+ SiHa cervical cancer cells. PKM2 knockdown also inhibited the E7-induced proliferation of cervical cancer cells. ML265 activating the pyruvate kinase function of PKM2 inhibited cell cycle progression and colony formation. ML265 treatments decreased phosphorylation of PKM2 at the Y105 position that has been associated with non-glycolytic functions. On the contrary, HPV16 E7 increased the PKM2 phosphorylation. Our results indicate that E7 increases PKM2 expression and activates a non-glycolytic function of PKM2 to promote cervical cancer cell proliferation.
23
Miao, Yi, Meng Lu, Qin Yan, Shuangdi Li, and Youji Feng. "Inhibition of Proliferation, Migration, and Invasion by Knockdown of Pyruvate Kinase-M2 (PKM2) in Ovarian Cancer SKOV3 and OVCAR3 Cells." Oncology Research Featuring Preclinical and Clinical Cancer Therapeutics 24, no. 6 (October 27, 2016): 463–75. http://dx.doi.org/10.3727/096504016x14685034103671.
Full textAbstract:
Pyruvate kinase (PK) is a key enzyme in the process of glycolysis, catalyzing phosphoenolpyruvate (PEP) into pyruvate. Currently, PK isozyme type M2 (PKM2), one subtype of PK, has been proposed as a new tumor marker with high expression in various tumor tissues. Here we aimed to explore the effects of siRNA-PKM2 on ovarian carcinoma (OC) cell lines SKOV3 and OVCAR3, in which PKM2 was notably expressed. PKM2 gene interference lentivirus vectors were built by miRNA transfection assay. siRNA-PKM2-transfected SKOV3 and OVCAR3 cells were evaluated for cell proliferation, cell cycle distribution, cell apoptosis, cell migration, and invasion in this study. In addition, the expression levels of several tumor-related genes were measured using real-time PCR and Western blot. Results showed that siRNA-PKM2 markedly inhibited cell proliferation, induced apoptosis, and caused cell cycle arrest at the G0/G1 phase. Cell migration and invasion were significantly suppressed by siRNA-PKM2. Furthermore, the tumor-related genes caspase 7, Bad, and E-cadherin were upregulated, while MMP2, HIF1α, VEGF, and MMP9 were depressed by siRNA-PKM2. The function of siRNA-PKM2 on the biological behavior of OC cells indicated that PKM2 may also be a target for treatment of OC.
24
Jiang, Lei, Yuanlin Gao, Gaiying Wang, and Jie Zhong. "PKM2 overexpression protects against 6-hydroxydopamine-induced cell injury in the PC12 cell model of Parkinson's disease via regulation of the brahma-related gene 1/STAT3 pathway." RSC Advances 9, no. 26 (2019): 14834–40. http://dx.doi.org/10.1039/c9ra01760g.
Full text
25
Biyik-Sit, Rumeysa, Traci Kruer, Susan Dougherty, James A. Bradley, Daniel W. Wilkey, Michael L. Merchant, John O. Trent, and Brian F. Clem. "Nuclear Pyruvate Kinase M2 (PKM2) Contributes to Phosphoserine Aminotransferase 1 (PSAT1)-Mediated Cell Migration in EGFR-Activated Lung Cancer Cells." Cancers 13, no. 16 (August 4, 2021): 3938. http://dx.doi.org/10.3390/cancers13163938.
Full textAbstract:
An elevated expression of phosphoserine aminotransferase 1 (PSAT1) has been observed in multiple tumor types and is associated with poorer clinical outcomes. Although PSAT1 is postulated to promote tumor growth through its enzymatic function within the serine synthesis pathway (SSP), its role in cancer progression has not been fully characterized. Here, we explore a putative non-canonical function of PSAT1 that contributes to lung tumor progression. Biochemical studies found that PSAT1 selectively interacts with pyruvate kinase M2 (PKM2). Amino acid mutations within a PKM2-unique region significantly reduced this interaction. While PSAT1 loss had no effect on cellular pyruvate kinase activity and PKM2 expression in non-small-cell lung cancer (NSCLC) cells, fractionation studies demonstrated that the silencing of PSAT1 in epidermal growth factor receptor (EGFR)-mutant PC9 or EGF-stimulated A549 cells decreased PKM2 nuclear translocation. Further, PSAT1 suppression abrogated cell migration in these two cell types whereas PSAT1 restoration or overexpression induced cell migration along with an elevated nuclear PKM2 expression. Lastly, the nuclear re-expression of the acetyl-mimetic mutant of PKM2 (K433Q), but not the wild-type, partially restored cell migration in PSAT1-silenced cells. Therefore, we conclude that, in response to EGFR activation, PSAT1 contributes to lung cancer cell migration, in part, by promoting nuclear PKM2 translocation.
26
Li, Qi, Xue Liu, Yu Yin, Ji-Tai Zheng, Cheng-Fei Jiang, Jing Wang, Hua Shen, et al. "Insulin Regulates Glucose Consumption and Lactate Production through Reactive Oxygen Species and Pyruvate Kinase M2." Oxidative Medicine and Cellular Longevity 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/504953.
Full textAbstract:
Although insulin is known to regulate glucose metabolism and closely associate with liver cancer, the molecular mechanisms still remain to be elucidated. In this study, we attempt to understand the mechanism of insulin in promotion of liver cancer metabolism. We found that insulin increased pyruvate kinase M2 (PKM2) expression through reactive oxygen species (ROS) for regulating glucose consumption and lactate production, key process of glycolysis in hepatocellular carcinoma HepG2 and Bel7402 cells. Interestingly, insulin-induced ROS was found responsible for the suppression of miR-145 and miR-128, and forced expression of either miR-145 or miR-128 was sufficient to abolish insulin-induced PKM2 expression. Furthermore, the knockdown of PKM2 expression also inhibited cancer cell growth and insulin-induced glucose consumption and lactate production, suggesting that PKM2 is a functional downstream effecter of insulin. Taken together, this study would provide a new insight into the mechanism of insulin-induced glycolysis.
27
Meoli, Luca, Nitin K. Gupta, Nima Saeidi, Courtney A. Panciotti, Sudha B. Biddinger, Kathleen E. Corey, and Nicholas Stylopoulos. "Nonalcoholic fatty liver disease and gastric bypass surgery regulate serum and hepatic levels of pyruvate kinase isoenzyme M2." American Journal of Physiology-Endocrinology and Metabolism 315, no. 4 (October 1, 2018): E613—E621. http://dx.doi.org/10.1152/ajpendo.00296.2017.
Full textAbstract:
Treatment of nonalcoholic fatty liver disease (NAFLD) focuses on the underlying metabolic syndrome, and Roux-en-Y gastric bypass surgery (RYGB) remains one of the most effective options. In rodents and human patients, RYGB induces an increase in the gene and protein expression levels of the M2 isoenzyme of pyruvate kinase (PKM2) in the jejunum. Since PKM2 can be secreted in the circulation, our hypothesis was that the circulating levels of PKM2 increase after RYGB. Our data, however, revealed an unexpected finding and a potential new role of PKM2 for the natural history of metabolic syndrome and NAFLD. Contrary to our initial hypothesis, RYGB-treated patients had decreased PKM2 blood levels compared with a well-matched group of patients with severe obesity before RYGB. Interestingly, PKM2 serum concentration correlated with body mass index before but not after the surgery. This prompted us to evaluate other potential mechanisms and sites of PKM2 regulation by the metabolic syndrome and RYGB. We found that in patients with NAFLD and nonalcoholic steatohepatitis (NASH), the liver had increased PKM2 expression levels, and the enzyme appears to be specifically localized in Kupffer cells. The study of murine models of metabolic syndrome and NASH replicated this pattern of expression, further suggesting a metabolic link between hepatic PKM2 and NAFLD. Therefore, we conclude that PKM2 serum and hepatic levels increase in both metabolic syndrome and NAFLD and decrease after RYGB. Thus, PKM2 may represent a new target for monitoring and treatment of NAFLD.
28
Li, Le, Lei Tang, Xiaoping Yang, Ruifang Chen, Zhen Zhang, Yiping Leng, and Alex F. Chen. "Gene Regulatory Effect of Pyruvate Kinase M2 is Involved in Renal Inflammation in Type 2 Diabetic Nephropathy." Experimental and Clinical Endocrinology & Diabetes 128, no. 09 (January 20, 2020): 599–606. http://dx.doi.org/10.1055/a-1069-7290.
Full textAbstract:
Abstract Background and Aims The inflammation of glomerular endothelial cells induces and promotes the activation of macrophages and contributes to the development of diabetic nephropathy. Thus, this study aimed to investigate the gene regulatory effect and potential role of pyruvate kinase M2 (PKM2) in inflammatory response in diabetic nephropathy. Methods The plasma PKM2 levels of patients with diabetes were evaluated. Eight-week-old mice were divided into three groups (WT, db/db mice, and db/db mice treated with TEPP-46) and raised for 12 weeks. Blood and kidney samples were collected at the end of the experiment. Endothelial cells were stimulated with high glucose with or without TEPP-46. The expression of intercellular adhesion molecule 1 (ICAM-1), interleukin 6 (IL-6), interleukin 1 beta (IL-1β), phospho-PKM2, PKM2, phospho-STAT3(signal transducer and activator of transcription), STAT3, nuclear factor kappa B (NF-kB), and phospho-NF-kB in vivo and in vitro were determined using Western blot. The activation of macrophages (CD68+CD86+) in the glomeruli was assessed via fluorescent double staining. Moreover, immune endothelial adhesion experiments were performed. Results The plasma PKM2 levels of patients with type 2 diabetes increased. P-PKM2 was up-regulated in vivo and in vitro. TEPP-46 decreased inflammatory cell infiltration and ICAM-1 expression in vivo and in vitro and inhibited the differentiation of macrophages to M1 cells in db/db mice with diabetic nephropathy. PKM2 regulated the phosphorylation of STAT3 and NF-kB. Furthermore, high glucose levels induced the transition from tetramer to dimer and the nuclear translocation of PKM2. Conclusion The gene regulatory effect of PKM2 is involved in renal inflammation in type 2 diabetic nephropathy by promoting the phosphorylation of STAT3 and NF-kB and the expression of intercellular adhesion molecule 1. Thus, the down-regulation of phosphorylated PKM2 may have protective effects against diabetic nephropathy by inhibiting renal inflammation.
29
Puckett, Dexter L., Mohammed Alquraishi, Winyoo Chowanadisai, and Ahmed Bettaieb. "The Role of PKM2 in Metabolic Reprogramming: Insights into the Regulatory Roles of Non-Coding RNAs." International Journal of Molecular Sciences 22, no. 3 (January 25, 2021): 1171. http://dx.doi.org/10.3390/ijms22031171.
Full textAbstract:
Pyruvate kinase is a key regulator in glycolysis through the conversion of phosphoenolpyruvate (PEP) into pyruvate. Pyruvate kinase exists in various isoforms that can exhibit diverse biological functions and outcomes. The pyruvate kinase isoenzyme type M2 (PKM2) controls cell progression and survival through the regulation of key signaling pathways. In cancer cells, the dimer form of PKM2 predominates and plays an integral role in cancer metabolism. This predominance of the inactive dimeric form promotes the accumulation of phosphometabolites, allowing cancer cells to engage in high levels of synthetic processing to enhance their proliferative capacity. PKM2 has been recognized for its role in regulating gene expression and transcription factors critical for health and disease. This role enables PKM2 to exert profound regulatory effects that promote cancer cell metabolism, proliferation, and migration. In addition to its role in cancer, PKM2 regulates aspects essential to cellular homeostasis in non-cancer tissues and, in some cases, promotes tissue-specific pathways in health and diseases. In pursuit of understanding the diverse tissue-specific roles of PKM2, investigations targeting tissues such as the kidney, liver, adipose, and pancreas have been conducted. Findings from these studies enhance our understanding of PKM2 functions in various diseases beyond cancer. Therefore, there is substantial interest in PKM2 modulation as a potential therapeutic target for the treatment of multiple conditions. Indeed, a vast plethora of research has focused on identifying therapeutic strategies for targeting PKM2. Recently, targeting PKM2 through its regulatory microRNAs, long non-coding RNAs (lncRNAs), and circular RNAs (circRNAs) has gathered increasing interest. Thus, the goal of this review is to highlight recent advancements in PKM2 research, with a focus on PKM2 regulatory microRNAs and lncRNAs and their subsequent physiological significance.
30
James, Andrew D., Daniel A. Richardson, In-Whan Oh, Pishyaporn Sritangos, Thomas Attard, Lisa Barrett, and Jason I. E. Bruce. "Cutting off the fuel supply to calcium pumps in pancreatic cancer cells: role of pyruvate kinase-M2 (PKM2)." British Journal of Cancer 122, no. 2 (December 10, 2019): 266–78. http://dx.doi.org/10.1038/s41416-019-0675-3.
Full textAbstract:
Abstract Background Pancreatic ductal adenocarcinoma (PDAC) has poor survival and treatment options. PDAC cells shift their metabolism towards glycolysis, which fuels the plasma membrane calcium pump (PMCA), thereby preventing Ca2+-dependent cell death. The ATP-generating pyruvate kinase-M2 (PKM2) is oncogenic and overexpressed in PDAC. This study investigated the PKM2-derived ATP supply to the PMCA as a potential therapeutic locus. Methods PDAC cell growth, migration and death were assessed by using sulforhodamine-B/tetrazolium-based assays, gap closure assay and poly-ADP ribose polymerase (PARP1) cleavage, respectively. Cellular ATP and metabolism were assessed using luciferase/fluorescent-based assays and the Seahorse XFe96 analyzer, respectively. Cell surface biotinylation identified membrane-associated proteins. Fura-2 imaging was used to assess cytosolic Ca2+ overload and in situ Ca2+ clearance. PKM2 knockdown was achieved using siRNA. Results The PKM2 inhibitor (shikonin) reduced PDAC cell proliferation, cell migration and induced cell death. This was due to inhibition of glycolysis, ATP depletion, inhibition of PMCA and cytotoxic Ca2+ overload. PKM2 associates with plasma membrane proteins providing a privileged ATP supply to the PMCA. PKM2 knockdown reduced PMCA activity and reduced the sensitivity of shikonin-induced cell death. Conclusions Cutting off the PKM2-derived ATP supply to the PMCA represents a novel therapeutic strategy for the treatment of PDAC.
31
Ouyang, Xinxing, Yuheng Han, Guojun Qu, Man Li, Ningbo Wu, Hongzhi Liu, Omotooke Arojo, et al. "Metabolic regulation of T cell development by Sin1–mTORC2 is mediated by pyruvate kinase M2." Journal of Molecular Cell Biology 11, no. 2 (November 14, 2018): 93–106. http://dx.doi.org/10.1093/jmcb/mjy065.
Full textAbstract:
Abstract Glucose metabolism plays a key role in thymocyte development. The mammalian target of rapamycin complex 2 (mTORC2) is a critical regulator of cell growth and metabolism, but its role in early thymocyte development and metabolism has not been fully studied. We show here that genetic ablation of Sin1, an essential component of mTORC2, in T lineage cells results in severely impaired thymocyte development at the CD4−CD8− double negative (DN) stages but not at the CD4+CD8+ double positive (DP) or later stages. Notably, Sin1-deficient DN thymocytes show markedly reduced proliferation and glycolysis. Importantly, we discover that the M2 isoform of pyruvate kinase (PKM2) is a novel and crucial Sin1 effector in promoting DN thymocyte development and metabolism. At the molecular level, we show that Sin1–mTORC2 controls PKM2 expression through an AKT-dependent PPAR-γ nuclear translocation. Together, our study unravels a novel mTORC2−PPAR-γ−PKM2 pathway in immune-metabolic regulation of early thymocyte development.
32
Ren, JunYu, Wenliang Li, Guoqing Pan, Fengchang Huang, Jun Yang, Hongbin Zhang, Ruize Zhou, and Ning Xu. "miR-142-3p Modulates Cell Invasion and Migration via PKM2-Mediated Aerobic Glycolysis in Colorectal Cancer." Analytical Cellular Pathology 2021 (July 13, 2021): 1–8. http://dx.doi.org/10.1155/2021/9927720.
Full textAbstract:
Decreased expression of miR-142-3p was observed in human cancers. However, the function and mechanism of miR-142-3p in human colorectal cancer remain obscure. The expressions of miR-142-3p in human colorectal cancer tissues and cell lines were measured by RT-qPCR. The effects of miR-142-3p on cell invasion and migration were detected by transwell assays. The efficiency of aerobic glycolysis was determined by glucose consumption and lactate production. Dual-luciferase reporter assays were performed to confirm the correlation between miR-142-3p and pyruvate kinase isozyme M2 (PKM2). The level of PKM2 was assessed by western blotting. Our results showed that the expression of miR-142-3p was decreased both in human colorectal cancer tissues and in cells. Overexpression of miR-142-3p in cell line attenuated colorectal cancer cell invasion and migration. About the underlying mechanism, we found that miR-142-3p modulated aerobic glycolysis via targeting pyruvate kinase M2 (PKM2). In addition, we demonstrated PKM2 and PKM2-mediated aerobic glycolysis contributes to miR-142-3p-mediated colorectal cancer cell invasion and migration. Hence, these data suggested that miR-142-3p was a potential therapeutic target for the treatment of human colorectal cancer.
33
Zhao, Xuezhu, Fancheng Tan, Xiaoru Cao, Zhengyu Cao, Bicheng Li, Zhaoqian Shen, and Ye Tian. "PKM2-dependent glycolysis promotes the proliferation and migration of vascular smooth muscle cells during atherosclerosis." Acta Biochimica et Biophysica Sinica 52, no. 1 (December 23, 2019): 9–17. http://dx.doi.org/10.1093/abbs/gmz135.
Full textAbstract:
Abstract Increased glycolysis is involved in the proliferation and migration of vascular smooth muscle cells (VSMCs). Pyruvate kinase isoform M2 (PKM2), a key rate-limiting enzyme in glycolysis, accelerates the proliferation and migration of tumor cells. Although the intracellular mechanisms associated with oxidized low-density lipoprotein (oxLDL)-stimulated VSMC proliferation and migration have been extensively explored, it is still unclear whether oxLDL promotes the proliferation and migration of VSMCs by enhancing PKM2-dependent glycolysis. In the present study, we detected PKM2 expression and pyruvate kinase activity in oxLDL-treated VSMCs and explored the regulation of PKM2 in oxLDL-treated VSMCs and apoE−/− mice. The results showed that PKM2 expression in VSMCs was higher in the intima than in the media in plaques from atherosclerotic rabbits. Moreover, PKM2 level in VSMCs was increased during atherosclerosis progression in apoE−/− mice. Both PKM2 expression and pyruvate kinase activity were found to be upregulated by oxLDL stimulation in VSMCs. Shikonin (SKN), a specific inhibitor of PKM2, was found to inhibit the oxLDL-induced proliferation and migration in VSMCs, in addition to delaying the atherosclerosis progression in apoE−/− mice. More importantly, oxLDL increased glucose uptake, ATP and lactate production, and the extracellular acidification rate in VSMCs, which could be reversed by SKN. Meanwhile, oxygen consumption rate was unchanged after oxLDL stimulation, suggesting that glycolysis is the main contributor to the energy supply in oxLDL-treated VSMCs. Our results suggest that oxLDL induces VSMC proliferation and migration by upregulating PKM2-dependent glycolysis, thereby contributing to the atherosclerosis progression. Thus, targeting PKM2-dependent glycolysis might provide a novel therapeutic approach for the treatment of atherosclerosis.
34
Li, Yunfeng, Yongsheng Chang, Lifeng Zhang, Qiping Feng, Zhuo Liu, Yongwei Zhang, Jin Zuo, Yan Meng, and Fude Fang. "High glucose upregulates pantothenate kinase 4 (PanK4) and thus affects M2-type pyruvate kinase (Pkm2)." Molecular and Cellular Biochemistry 277, no. 1-2 (September 2005): 117–25. http://dx.doi.org/10.1007/s11010-005-5535-1.
Full text
35
Yuan, Peng, Yiyi Zhou, Rui Wang, Shayang Chen, Qiqi Wang, Zhujie Xu, Yi Liu, and Huilin Yang. "TRIM58 Interacts with Pyruvate Kinase M2 to Inhibit Tumorigenicity in Human Osteosarcoma Cells." BioMed Research International 2020 (March 7, 2020): 1–9. http://dx.doi.org/10.1155/2020/8450606.
Full textAbstract:
Background. Tripartite motif containing 58 (TRIM58), an E3 ubiquitin ligase, is reported as a suppressor gene in certain human tumors. However, the biological function of TRIM58 in osteosarcoma (OS) is still less identified. Methods. In the present study, TRIM58 induced silencing and overexpression in OS cells using RNA interference (RNAi) and lentiviral-mediated vector, respectively. Cell proliferation profiles were analyzed using cell counting kit-8 (CCK-8) assay. Cell apoptosis profiles were determined using a flow cytometer. qRT-PCR and western blot were used to determine gene expression. Coimmunoprecipitation (Co-IP) assay was used to examine protein interaction. Results. Our results demonstrated TRIM58 was downregulated in human OS tissues. Overexpression of TRIM58 remarkably suppressed the growth of OS cells and decreased glucose transportation and lactate secretion. These results indicated that TRIM58 involved in the regulation of energy metabolism in OS cells. Importantly, TRIM58 interacted with pyruvate kinase M2 (PKM2) in OS cells. Moreover, TRIM58 might inhibit the activity of PKM2 through enhancing its polyubiquitination in OS cells. Conclusions. This analysis not only explored a deep understanding of the biological function of TRIM58 but also indicated its signaling pathway in OS cells.
36
Wong, Nicholas, Jason De Melo, and Damu Tang. "PKM2, a Central Point of Regulation in Cancer Metabolism." International Journal of Cell Biology 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/242513.
Full textAbstract:
Aerobic glycolysis is the dominant metabolic pathway utilized by cancer cells, owing to its ability to divert glucose metabolites from ATP production towards the synthesis of cellular building blocks (nucleotides, amino acids, and lipids) to meet the demands of proliferation. The M2 isoform of pyruvate kinase (PKM2) catalyzes the final and also a rate-limiting reaction in the glycolytic pathway. In the PK family, PKM2 is subjected to a complex regulation by both oncogenes and tumour suppressors, which allows for a fine-tone regulation of PKM2 activity. The less active form of PKM2 drives glucose through the route of aerobic glycolysis, while active PKM2 directs glucose towards oxidative metabolism. Additionally, PKM2 possesses protein tyrosine kinase activity and plays a role in modulating gene expression and thereby contributing to tumorigenesis. We will discuss our current understanding of PKM2's regulation and its many contributions to tumorigenesis.
37
Mohammad, Goran Hamid, Vessela Vassileva, Pilar Acedo, Steven W. M. Olde Damink, Massimo Malago, Dipok Kumar Dhar, and Stephen P. Pereira. "Targeting Pyruvate Kinase M2 and Lactate Dehydrogenase A Is an Effective Combination Strategy for the Treatment of Pancreatic Cancer." Cancers 11, no. 9 (September 16, 2019): 1372. http://dx.doi.org/10.3390/cancers11091372.
Full textAbstract:
Reprogrammed glucose metabolism is one of the hallmarks of cancer, and increased expression of key glycolytic enzymes, such as pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA), has been associated with poor prognosis in various malignancies. Targeting these enzymes could attenuate aerobic glycolysis and inhibit tumor proliferation. We investigated whether the PKM2 activator, TEPP-46, and the LDHA inhibitor, FX-11, can be combined to inhibit in vitro and in vivo tumor growth in preclinical models of pancreatic cancer. We assessed PKM2 and LDHA expression, enzyme activity, and cell proliferation rate after treatment with TEPP-46, FX-11, or a combination of both. Efficacy was validated in vivo by evaluating tumor growth, PK and LDHA activity in plasma and tumors, and PKM2, LDHA, and Ki-67 expression in tumor tissues following treatment. Dual therapy synergistically inhibited pancreatic cancer cell proliferation and significantly delayed tumor growth in vivo without apparent toxicity. Treatment with TEPP-46 and FX-11 resulted in increased PK and reduced LDHA enzyme activity in plasma and tumor tissues and decreased PKM2 and LDHA expression in tumors, which was reflected by a decrease in tumor volume and proliferation. The targeting of glycolytic enzymes such as PKM2 and LDHA represents a promising therapeutic approach for the treatment of pancreatic cancer.
38
Zheng, Mengying, Chunyan Liu, Yuanyuan Shao, Rong Fu, Huaquan Wang, Ting Wang, Weiwei Qi, and Zonghong Shao. "The Effect of Pyruvate Kinase M2: Inhibitor(shikonin) on the Function of Mdc in Severe Aplastic Anemia Mouse Model." Blood 134, Supplement_1 (November 13, 2019): 5021. http://dx.doi.org/10.1182/blood-2019-126726.
Full textAbstract:
Severe aplastic anemia (SAA) is a rare disease characterized by severe pancytopenia and bone marrow failure. Over-activated myeloid dendritic cells (mDCs) play an important role in the pathogenesis of SAA. In recent years, the role of pyruvate kinase M2 (PKM2) in DC function and autoimmune response has been gradually recognized. In this study, an immune attack-mediated AA mouse model was constructed by total body irradiation and lymphocyte infusion. The AA model mice showed pancytopenia, decreased ratio of CD4+/CD8+ cells, increased expression of cytotoxic molecules perforin and granzyme in CD8+ cells, increased levels of co-stimulatory molecules CD80 and CD86 in DCs and inadequate Treg number. In-vitro animal experiments confirmed the activation of PKM2 in mDCs, which promoted glycolytic metabolism. High levels of PKM2 in mice contributed to the poor survival rate. Additionally, intervention treatment with shikonin or cyclosporin A in the AA mouse model reduced the expression not only of co-stimulatory molecules CD80 and CD86 in mDCs but also of cytotoxic molecules in CD8+ cells. In conclusion, we confirmed the activation of PKM2 in mDCs in AA mouse models. PKM2 is involved in mDC activation and proliferation, which might contribute to activating the downstream cytotoxic T cells (CTLs). PKM2 is a possible novel target in SAA treatment. Disclosures No relevant conflicts of interest to declare.
39
Shao, Zonghong, and Mengying Zheng. "Abnormal Levels of PKM2 in Mdcs from Patients with Severe Aplastic." Blood 126, no. 23 (December 3, 2015): 4766. http://dx.doi.org/10.1182/blood.v126.23.4766.4766.
Full textAbstract:
Abstract Severe aplastic anemia (SAA) is a hematologic disease characterized by pancytopenia with severe bone marrow failure. Our previous studies have demonstrated that activated myeloid dendritic cells (mDCs) increased in the bone marrow of SAA patients, which might promote Th0 cells to polarize to Th1 cells and cause the subsequent over-function of T lymphocytes and hematopoiesis failure in SAA. The other notable finding in our study is that abnormal expression of pyruvate kinase M2 (PKM2) in mDCs from SAA patients may be one of the reason for mDC hyperfunction. Human pyruvate kinase M2, which catalyzes the last but rate-limiting step of glycolysis, is exclusively expressed in actively proliferated cells ,especially in embryonic and adult dividing/tumor cells. It remains unclear how PKM2 may change in patients with SAA. This study aims at exploring the role of PKM2 in SAA. In this study, the quantitative changes of mDCs in peripheral blood of 15 SAA patients before immunosuppressive therapy (IST) °¢ 13 SAA patients after IST and 26 normal controls were determined by flow cytometry. Results showed that the levels of PKM2 in mDCs were significantly increased in SAA patients(59.1±15.8)%. After IST, the levels of PKM2 in mDCs decreased(42.6±22.1)% (P<0.05).In normal controls group , the level of PKM2 in mDCs was (32.7±20.2)%. These changes reveal that dysregulation of PKM2 expression and activation in mDCs from SAA patients may contribute to hyperfunction of mDCs, thus leading to the imbalance of downstream Th1/Th2 subsets which followed by hematopoiesis failure in SAA. Figure 1. Figure 1. Disclosures No relevant conflicts of interest to declare.
40
Irokawa, Hayato, Satoshi Numasaki, Shin Kato, Kenta Iwai, Atsushi Inose-Maruyama, Takumi Ohdate, Gi-Wook Hwang, Takashi Toyama, Toshihiko Watanabe, and Shusuke Kuge. "Comprehensive analyses of the cysteine thiol oxidation of PKM2 reveal the effects of multiple oxidation on cellular oxidative stress response." Biochemical Journal 478, no. 7 (April 16, 2021): 1453–70. http://dx.doi.org/10.1042/bcj20200897.
Full textAbstract:
Redox regulation of proteins via cysteine residue oxidation is involved in the control of various cellular signal pathways. Pyruvate kinase M2 (PKM2), a rate-limiting enzyme in glycolysis, is critical for the metabolic shift from glycolysis to the pentose phosphate pathway under oxidative stress in cancer cell growth. The PKM2 tetramer is required for optimal pyruvate kinase (PK) activity, whereas the inhibition of inter-subunit interaction of PKM2 induced by Cys358 oxidation has reduced PK activity. In the present study, we identified three oxidation-sensitive cysteine residues (Cys358, Cys423 and Cys424) responsible for four oxidation forms via the thiol oxidant diamide and/or hydrogen peroxide (H2O2). Possibly due to obstruction of the dimer-dimer interface, H2O2-induced sulfenylation (-SOH) and diamide-induced modification at Cys424 inhibited tetramer formation and PK activity. Cys423 is responsible for intermolecular disulfide bonds with heterologous proteins via diamide. Additionally, intramolecular polysulphide linkage (–Sn–, n ≧ 3) between Cys358 and an unidentified PKM2 Cys could be induced by diamide. We observed that cells expressing the oxidation-resistant PKM2 (PKM2C358,424A) produced more intracellular reactive oxygen species (ROS) and exhibited greater sensitivity to ROS-generating reagents and ROS-inducible anti-cancer drugs compared with cells expressing wild-type PKM2. These results highlight the possibility that PKM2 inhibition via Cys358 and Cys424 oxidation contributes to eliminating excess ROS and oxidative stress.
41
Bhardwaj, Abhishek, and Sanjeev Das. "SIRT6 deacetylates PKM2 to suppress its nuclear localization and oncogenic functions." Proceedings of the National Academy of Sciences 113, no. 5 (January 19, 2016): E538—E547. http://dx.doi.org/10.1073/pnas.1520045113.
Full textAbstract:
SIRT6 (sirtuin 6) is a member of sirtuin family of deacetylases involved in diverse processes including genome stability, metabolic homeostasis, and tumorigenesis. However, the role of SIRT6 deacetylase activity in its tumor-suppressor functions is not well understood. Here we report that SIRT6 binds to and deacetylates nuclear PKM2 (pyruvate kinase M2) at the lysine 433 residue. PKM2 is a glycolytic enzyme with nonmetabolic nuclear oncogenic functions. SIRT6-mediated deacetylation results in PKM2 nuclear export. We further have identified exportin 4 as the specific transporter mediating PKM2 nuclear export. As a result of SIRT6-mediated deacetylation, PKM2 nuclear protein kinase and transcriptional coactivator functions are abolished. Thus, SIRT6 suppresses PKM2 oncogenic functions, resulting in reduced cell proliferation, migration potential, and invasiveness. Furthermore, studies in mouse tumor models demonstrate that PKM2 deacetylation is integral to SIRT6-mediated tumor suppression and inhibition of metastasis. Additionally, reduced SIRT6 levels correlate with elevated nuclear acetylated PKM2 levels in increasing grades of hepatocellular carcinoma. These findings provide key insights into the pivotal role of deacetylase activity in SIRT6 tumor-suppressor functions.
42
Zhu, Haiyan, Hui Luo, Xuejie Zhu, Xiaoli Hu, Lihong Zheng, and Xueqiong Zhu. "Pyruvate kinase M2 (PKM2) expression correlates with prognosis in solid cancers: a meta-analysis." Oncotarget 8, no. 1 (November 29, 2016): 1628–40. http://dx.doi.org/10.18632/oncotarget.13703.
Full text
43
He, Yunhua, Yuchan Wang, Hong Liu, Xiaohong Xu, Song He, Jie Tang, Yuejiao Huang, et al. "Pyruvate kinase isoform M2 (PKM2) participates in multiple myeloma cell proliferation, adhesion and chemoresistance." Leukemia Research 39, no. 12 (December 2015): 1428–36. http://dx.doi.org/10.1016/j.leukres.2015.09.019.
Full text
44
Lai, Chou, Lin, Yu, Ou, Chu, Wu, Wang, and Chao. "Pyruvate Kinase M2 Expression: A Potential Metabolic Biomarker to Differentiate Endometrial Precancer and Cancer That Is Associated with Poor Outcomes in Endometrial Carcinoma." International Journal of Environmental Research and Public Health 16, no. 23 (November 20, 2019): 4589. http://dx.doi.org/10.3390/ijerph16234589.
Full textAbstract:
Background: Pyruvate kinase M2 (PKM2) is a regulator of the processes of glycolysis and oxidative phosphorylation, but the roles that it plays in endometrial cancer remain largely unknown. This study evaluated the PKM2 expression in normal endometrium, endometrial hyperplasia, and endometrial carcinoma, and its prognostic value was investigated in endometrial carcinoma patients. Methods: A hospital-based retrospective review was conducted to examine the immunohistochemical PKM2 distribution in 206 endometrium samples from biopsies or hysterectomies. The immunoreactivity of PKM2 was divided into groups of low and high scores according to the extent and intensity of staining. Results: Intense cytoplasmic staining was observed for the PKM2 protein in malignant endometrial lesions. A high PKM2 score was observed in many endometrial carcinoma samples (50.0%), but there was a low percentage in endometrial atypical hyperplasia (12.5%). High PKM2 expression was not found in the normal endometrium (0.0%) nor endometrial hyperplasia without atypia (0.0%). The PKM2 protein score was significantly higher in endometrial carcinoma samples than premalignant endometrial lesions (p < 0.001). Notably, higher PKM2 scores in cases of endometrial carcinoma correlated with poor overall survival (p = 0.006), and the hazard ratio for death was 3.40 (95% confidence interval, 1.35–8.56). Conclusions: Our results indicate that the prevalence of PKM2high tumor cells in endometrial carcinoma is significantly associated with worse prognostic factors and favors a poor prognosis. The expression of PKM2 is also a potential histopathological biomarker for use in the differential diagnosis of malignant and premalignant endometrial lesions.
45
Le, Sheng, Hao Zhang, Xiaofan Huang, Shu Chen, Jia Wu, Shanshan Chen, XiangChao Ding, et al. "PKM2 Activator TEPP-46 Attenuates Thoracic Aortic Aneurysm and Dissection by Inhibiting NLRP3 Inflammasome-Mediated IL-1β Secretion." Journal of Cardiovascular Pharmacology and Therapeutics 25, no. 4 (April 23, 2020): 364–76. http://dx.doi.org/10.1177/1074248420919966.
Full textAbstract:
Background: The development of thoracic aortic aneurysm and dissection (TAAD) is mediated by inflammasome activation, which exacerbates the secretion of pro-inflammatory cytokines, chemokines, matrix metalloproteinases (MMPs), and reactive oxygen species (ROS). The glycolytic enzyme pyruvate kinase M2 (PKM2) has shown a protective role against various disorders with an inflammatory basis, such as sepsis, tumorigenesis, and diabetic nephropathy. However, its potential role in TAAD has not been investigated so far. Approach and Results: We analyzed aortic tissues from TAAD patients and the β-aminopropionitrile fumarate (BAPN)–induced mouse model of TAAD and observed elevated levels of PKM2 in the aortic lesions of both. Treatment with the PKM2 activator TEPP-46 markedly attenuated the progression of TAAD in the mouse model as demonstrated by decreased morbidity and luminal diameter of the aorta. In addition, the thoracic aortas of the BAPN-induced mice showed reduced monocytes and macrophages infiltration and lower levels of IL-1β, MMPs, and ROS when treated with TEPP-46. Furthermore, TEPP-46 treatment also suppressed the activation of the NOD-like receptor (NLR) family and pyrin domain–containing protein 3 (NLRP3) inflammasome by downregulating p-STAT3 and HIF1-α. Conclusion: Pyruvate kinase M2 plays a protective role in TAAD development, and its activation is a promising therapeutic strategy against the progression of TAAD.
46
Li, Ning, Dandan Meng, Yue Xu, Ling Gao, Fengqian Shen, Xiaojing Tie, Yan Zhang, et al. "Pyruvate Kinase M2 Knockdown Suppresses Migration, Invasion, and Epithelial-Mesenchymal Transition of Gastric Carcinoma via Hypoxia-Inducible Factor Alpha/B-Cell Lymphoma 6 Pathway." BioMed Research International 2020 (December 9, 2020): 1–10. http://dx.doi.org/10.1155/2020/7467104.
Full textAbstract:
Gastric carcinoma is a common malignant cancer. Pyruvate kinase M2 (PKM2) is highly expressed in cancers, including gastric carcinoma. However, its function and molecular mechanism in gastric carcinoma remains unclear. Here, we aimed to explore the function and the underlying mechanism of PKM2 on malignant phenotypes in gastric carcinoma. In this study, the mRNA levels and protein levels of PKM2 in gastric carcinoma cell lines and normal gastric mucosa epithelial cell lines were detected using quantitative real-time PCR and western blot, respectively. PKM2 was downregulated by siRNA transfection. HIF-1α or BCL-6 was upregulated by corresponding overexpression plasmid. Cell viability was detected using CCK-8 assay. Cell invasion and migration were determined using transwell assay. Higher expression of PKM2 was observed in human gastric carcinoma cell lines MKN-45 and SGC-7901 than in the normal gastric mucosa epithelial cell line GES-1. PKM2 knockdown suppressed cancer cell invasion and migration and inhibited the epithelial-mesenchymal transition (EMT) phenotype by inhibiting E-cadherin and promoting vimentin and N-cadherin expression. Also, we observed that PKM2 knockdown suppressed the hypoxia-inducible factor alpha (HIF-1α) and B-cell lymphoma 6 (BCL-6) signaling pathway. HIF-1α overexpression reversed the function of PKM2 silencing on cell invasion, migration, EMT, and BCL-6 expression. BCL-6 overexpression also reversed the function of PKM2 silencing on cell invasion, migration, and EMT but did not affect HIF-1α expression. Taken together, data from our study suggest that PKM2 knockdown impeded cell migration, invasion, and EMT of gastric carcinoma cells via the HIF-1α/BCL-6 pathway.
47
Shirai, Tsuyoshi, Rafal R. Nazarewicz, Barbara B. Wallis, Rolando E. Yanes, Ryu Watanabe, Marc Hilhorst, Lu Tian, et al. "The glycolytic enzyme PKM2 bridges metabolic and inflammatory dysfunction in coronary artery disease." Journal of Experimental Medicine 213, no. 3 (February 29, 2016): 337–54. http://dx.doi.org/10.1084/jem.20150900.
Full textAbstract:
Abnormal glucose metabolism and enhanced oxidative stress accelerate cardiovascular disease, a chronic inflammatory condition causing high morbidity and mortality. Here, we report that in monocytes and macrophages of patients with atherosclerotic coronary artery disease (CAD), overutilization of glucose promotes excessive and prolonged production of the cytokines IL-6 and IL-1β, driving systemic and tissue inflammation. In patient-derived monocytes and macrophages, increased glucose uptake and glycolytic flux fuel the generation of mitochondrial reactive oxygen species, which in turn promote dimerization of the glycolytic enzyme pyruvate kinase M2 (PKM2) and enable its nuclear translocation. Nuclear PKM2 functions as a protein kinase that phosphorylates the transcription factor STAT3, thus boosting IL-6 and IL-1β production. Reducing glycolysis, scavenging superoxide and enforcing PKM2 tetramerization correct the proinflammatory phenotype of CAD macrophages. In essence, PKM2 serves a previously unidentified role as a molecular integrator of metabolic dysfunction, oxidative stress and tissue inflammation and represents a novel therapeutic target in cardiovascular disease.
48
Cho, Eun-Seok, Hyeon-Jeong Jeon, Si-Woo Lee, Jong-Woon Park, Sebastian Raveendar, Gul-Won Jang, Tae-Hun Kim, and Kyung-Tai Lee. "Association of a Pyruvate Kinase M2 (PKM2) Polymorphism with Back Fat Thickness in Berkshire Pigs." Journal of Animal Science and Technology 55, no. 6 (December 31, 2013): 515–20. http://dx.doi.org/10.5187/jast.2013.55.6.515.
Full text
49
Lee, Jungwoon, Hye Kyoung Kim, Yong-Mahn Han, and Jungho Kim. "Pyruvate kinase isozyme type M2 (PKM2) interacts and cooperates with Oct-4 in regulating transcription." International Journal of Biochemistry & Cell Biology 40, no. 5 (January 2008): 1043–54. http://dx.doi.org/10.1016/j.biocel.2007.11.009.
Full text
50
Almousa, Ahmed A., Marc Morris, Sharyle Fowler, Jennifer Jones, and Jane Alcorn. "Elevation of serum pyruvate kinase M2 (PKM2) in IBD and its relationship to IBD indices." Clinical Biochemistry 53 (March 2018): 19–24. http://dx.doi.org/10.1016/j.clinbiochem.2017.12.007.
Full text