Journal articles: 'Reverse Warburg effect'

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Xu, Xiao Dong, Shi Xiu Shao, Hai Ping Jiang, Yan Wei Cao, Yong Hua Wang, Xue Cheng Yang, You Lin Wang, Xin Sheng Wang, and Hai Tao Niu. "Warburg Effect or Reverse Warburg Effect? A Review of Cancer Metabolism." Oncology Research and Treatment 38, no. 3 (2015): 117–22. http://dx.doi.org/10.1159/000375435.

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Sotgia, Federica, Ubaldo E. Martinez-Outschoorn, and Michael P. Lisanti. "The reverse warburg effect in osteosarcoma." Oncotarget 5, no. 18 (August 15, 2014): 7982–83. http://dx.doi.org/10.18632/oncotarget.2352.

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Gonzalez, Claudio D., Silvia Alvarez, Alejandro Ropolo, Carla Rosenzvit, Maria F. Gonzalez Bagnes, and Maria I. Vaccaro. "Autophagy, Warburg, and Warburg Reverse Effects in Human Cancer." BioMed Research International 2014 (2014): 1–10. http://dx.doi.org/10.1155/2014/926729.

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Autophagy is a highly regulated-cell pathway for degrading long-lived proteins as well as for clearing cytoplasmic organelles. Autophagy is a key contributor to cellular homeostasis and metabolism. Warburg hypothesized that cancer growth is frequently associated with a deviation of a set of energy generation mechanisms to a nonoxidative breakdown of glucose. This cellular phenomenon seems to rely on a respiratory impairment, linked to mitochondrial dysfunction. This mitochondrial dysfunction results in a switch to anaerobic glycolysis. It has been recently suggested that epithelial cancer cells may induce the Warburg effect in neighboring stromal fibroblasts in which autophagy was activated. These series of observations drove to the proposal of a putative reverse Warburg effect of pathophysiological relevance for, at least, some tumor phenotypes. In this review we introduce the autophagy process and its regulation and its selective pathways and role in cancer cell metabolism. We define and describe the Warburg effect and the newly suggested “reverse” hypothesis. We also discuss the potential value of modulating autophagy with several pharmacological agents able to modify the Warburg effect. The association of the Warburg effect in cancer and stromal cells to tumor-related autophagy may be of relevance for further development of experimental therapeutics as well as for cancer prevention.

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Benny, Sonu, Rohan Mishra, Maneesha K. Manojkumar, and T. P. Aneesh. "From Warburg effect to Reverse Warburg effect; the new horizons of anti-cancer therapy." Medical Hypotheses 144 (November 2020): 110216. http://dx.doi.org/10.1016/j.mehy.2020.110216.

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Shan, Mengrou, David Dai, Arunodai Vudem, Jeffrey D. Varner, and Abraham D. Stroock. "Multi-scale computational study of the Warburg effect, reverse Warburg effect and glutamine addiction in solid tumors." PLOS Computational Biology 14, no. 12 (December 7, 2018): e1006584. http://dx.doi.org/10.1371/journal.pcbi.1006584.

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Strunová, Marie, David Pavlišta, Jitka Kobilková, Jiří Pokorný, Miloslav Janoušek, Lenka Bauerová, and Anna Jandová. "Is the Small Size of a Breast Cancer Tumor the Crucial Point for Successful Medical Treatment?" Prague Medical Report 115, no. 3-4 (2014): 134–40. http://dx.doi.org/10.14712/23362936.2014.44.

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The presented case displays a clinical study of a cancer phenotype with a poor clinical outcome. Prediction of cancer development and effects of treatment at the beginning of the clinical stage is difficult as the knowledge of cancer process and all necessary parameters of the host body are limited. Cancer is mainly studied on the basis of biochemical-genetic processes and their morphological manifestation. However, the malignant process is assumed to be of essential biophysical nature and develops after mitochondrial dysfunction, which is a direct result of oncogene mutation. Cancers based on the normal and the reverse Warburg effect should be distinguished. The cancer tumors with the reverse Warburg effect display aggressiveness associated with a high rate of recurrence and metastatic implantation. Besides the nature of the two basic types of breast cancer tumors the outcome depends not only on their type, size, and site but also on reactions and interaction with the surrounding tissue and the body aptitude for metastatic activity connected with individual blood or lymphatic vessels for metastatic transport. It is necessary to assess all favourable and adverse factors for cancer development. General reliable method of their specification for all cancers is not available. Nevertheless, the main factor seems to be aggressiveness of cancer cells as follows from interpretation. To reveal the aggressive reverse Warburg effect tumors, metabolic biomarkers of the fibroblast stress should be examined.

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Pokorný, Jiří, Jan Pokorný, Jitka Kobilková, Anna Jandová, Jan Vrba, and Jan Vrba. "Targeting Mitochondria for Cancer Treatment – Two Types of Mitochondrial Dysfunction." Prague Medical Report 115, no. 3-4 (2014): 104–19. http://dx.doi.org/10.14712/23362936.2014.41.

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Two basic types of cancers were identified – those with the mitochondrial dysfunction in cancer cells (the Warburg effect) or in fibroblasts supplying energy rich metabolites to a cancer cell with functional mitochondria (the reverse Warburg effect). Inner membrane potential of the functional and dysfunctional mitochondria measured by fluorescent dyes (e.g. by Rhodamine 123) displays low and high values (apparent potential), respectively, which is in contrast to the level of oxidative metabolism. Mitochondrial dysfunction (full function) results in reduced (high) oxidative metabolism, low (high) real membrane potential, a simple layer (two layers) of transported protons around mitochondria, and high (low) damping of microtubule electric polar vibrations. Crucial modifications are caused by ordered water layer (exclusion zone). For the high oxidative metabolism one proton layer is at the mitochondrial membrane and the other at the outer rim of the ordered water layer. High and low damping of electric polar vibrations results in decreased and increased electromagnetic activity in cancer cells with the normal and the reverse Warburg effect, respectively. Due to nonlinear properties the electromagnetic frequency spectra of cancer cells and transformed fibroblasts are shifted in directions corresponding to their power deviations resulting in disturbances of interactions and escape from tissue control. The cancer cells and fibroblasts of the reverse Warburg effect tumors display frequency shifts in mutually opposite directions resulting in early generalization. High oxidative metabolism conditions high aggressiveness. Mitochondrial dysfunction, a gate to malignancy along the cancer transformation pathway, forms a narrow neck which could be convenient for cancer treatment.

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Pokorný, Jiří, Jan Pokorný, Jitka Kobilková, Anna Jandová, and Robert Holaj. "Cancer Development and Damped Electromagnetic Activity." Applied Sciences 10, no. 5 (March 6, 2020): 1826. http://dx.doi.org/10.3390/app10051826.

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Cancer can be initiated in a cell or a fibroblast by short-circuiting of the cellular electromagnetic field by various fibers, parasitic energy consumption, virus infections, and mitochondrial defects, leading to a damped cellular electromagnetic field. Except short-circuiting (e.g., by asbestos fibers), the central process is mitochondrial dysfunction in cancer cells (the Warburg effect) or in fibroblasts associated with a cancer cell (the reverse Warburg effect), critically lowered respiration, reversed polarity of the ordered water layers around mitochondria, and damped electromagnetic activity of the affected cells. Frequency and power changes of the generated electromagnetic field result in broken communication between cells and possibly in reduced control over chemical reactions, with an increased probability of random genome mutations. An interdisciplinary framework of phenomena related to cancer development is presented, with special attention to the causes and consequences of disturbed cellular electromagnetic activity. Our framework extends the current knowledge of carcinogenesis, to clarify yet unexplained phenomena leading to genome mutation and cancer initiation.

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Evans, Laura A., Emilie I. Anderson, Xuan-Mai Petterson, Shaji Kumar, and Wilson I. Gonsalves. "Disrupting the Reverse Warburg Effect As a Therapeutic Strategy in Multiple Myeloma." Blood 138, Supplement 1 (November 5, 2021): 2649. http://dx.doi.org/10.1182/blood-2021-147970.

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Abstract Introduction: Altered cellular metabolism is a hallmark of every cancer cell. Aerobic glycolysis ("The Warburg Effect") is one of the earliest recognized metabolic abnormalities in cancer cells whereby extracellular glucose is preferentially metabolized and eventually processed to generate lactate and energy in the form of ATP before the former is released extracellularly, irrespective of oxygen availability. While extracellular lactate produced and released from cancer cells has traditionally been considered a waste metabolic by-product, recent understanding of cell metabolism suggests that it can also serve as a primary metabolic fuel for cancer cells via uptake by monocarboxylate transporters (MCTs). Our goal was to evaluate this "Reverse Warburg Effect" phenomenon in multiple myeloma (MM) cells and determine if it can be exploited for therapeutic purposes. Methods: All HMCLs, MM1S, RPMI-8226 and U266, were grown in RPMI-1640 cell culture medium containing 11 mM glucose and supplemented with 10% dialyzed fetal bovine serum (FBS) and 2 mM Glutamine. Primary MM cells were extracted using magnetic bead CD138 positive selection from MM patient bone marrow aspirates. For 13C-labeling experiments, HMCLs and primary MM cells were suspended in RPMI-1640 cell culture media containing 13C-labeled isotopes. Isotopomer analysis of glycolytic and tricarboxylic acid (TCA) cycle metabolites from HMCL and primary MM cell pellets was performed using Agilent Technologies 5975C gas chromatography-mass spectrometry. Small molecule inhibitors, AZD3965 and syrosingopine, were purchased from Selleck Chemicals and Sigma respectively. Cellular viability and proliferation were measured using 3-(4, 5-dimethylthiazol-2-yl)-2, 5-diphenyl tetrasodium bromide (MTT) and CCK-8 assays respectively. MCT-1 and MCT-4 antibodies for western blotting were utilized to evaluate their cell membrane expression on HMCLs. Results: The HMCLs, MM1S and RPMI-8226 as well as primary CD138+ cells from MM patient bone marrow were cultured in cell culture media containing physiological levels (1 mM) of U-13C-Lactate. The incorporation of extracellular 13C into the intracellular glycolytic and TCA cycle metabolite pool was observed (Fig 1) based on the expected isotopomeric patterns, demonstrating the Reverse Warburg Effect in MM cells. The relative contribution of carbon substrate by extracellular lactate compared to extracellular glucose was assessed in the following HMCLs: MM1S, RPMI-8226 and U266 cells by culturing in cell culture media containing 3-13C-Lactate and U-13C-Glucose. Extracellular lactate (yellow bar) contribution to the formation of TCA metabolites equaled that of glucose (red bar) based on the expected isotopomer patterns, suggesting the relative importance of extracellular lactate as an essential nutrient like glucose (Fig 2). Since MCT-1 and MCT-4 are key bidirectional cell membrane transporters of lactate in and out of cells, we explored the clinical significance of their gene expression level on clinical outcomes using the COMMPASS dataset provided by the Multiple Myeloma Research Foundation (MMRF). When MM patients were dichotomized at above or below the median of the expression levels of fragments per kilobase of transcript per million (FPKM), MCT-1 and MCT-4 overexpression conferred a worse progression free survival and overall survival (Fig 3). The MCT-1/MCT-4 protein expression was detectable across the various HMCLs: MM1S, U266 and RPMI-8226 (Fig 4). Inhibition of MCT-1 by specific inhibitor AZD3965 was able to reduce proliferation but not affect viability of HMCLs at 48 hours (Fig 5). However, dual inhibition of MCT-1/MCT-4 using syrosingopine was able to significantly reduce proliferation and decrease viability of HMCLs in a dose dependent fashion (Fig 6). Finally, dual inhibition of MCT-1/MCT-4 using syrosingopine reduced the utilization of extracellular lactate into the TCA cycle pool by HMCLs in media containing 3-13C-Lactate (Fig 7). Conclusion: Utilization of extracellular lactate via Reverse Warburg Effect phenomenon appears highly active in MM cells. Disrupting the utilization of extracellular lactate by dual inhibition of both MCT-1 and MCT-4 appears therapeutic. In the future, dual inhibition of MCT-1/MCT-4 in combination with other anti-MM therapies should be evaluated to determine synergistic therapeutic potential. Figure 1 Figure 1. Disclosures Kumar: Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Carsgen: Research Funding; Sanofi: Research Funding; Novartis: Research Funding; Antengene: Consultancy, Honoraria; Beigene: Consultancy; Bluebird Bio: Consultancy; Adaptive: Membership on an entity's Board of Directors or advisory committees, Research Funding; Tenebio: Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Oncopeptides: Consultancy; Astra-Zeneca: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Research Funding; Roche-Genentech: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding.

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Marshall, JL, J. Falconer, S. Kapoor, A. Filer, K. Raza, SP Young, and CD Buckley. "A3.04 Stromal cell metabolism; the reverse warburg effect in the inflamed synovium." Annals of the Rheumatic Diseases 75, Suppl 1 (February 2016): A33.3—A34. http://dx.doi.org/10.1136/annrheumdis-2016-209124.81.

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Witkiewicz, Agnieszka K., Diana Whitaker-Menezes, Abhijit Dasgupta, Nancy J. Philp, Zhao Lin, Ricardo Gandara, Sharon Sneddon, Ubaldo E. Martinez-Outschoorn, Federica Sotgia, and Michael P. Lisanti. "Using the “reverse Warburg effect” to identify high-risk breast cancer patients." Cell Cycle 11, no. 6 (March 15, 2012): 1108–17. http://dx.doi.org/10.4161/cc.11.6.19530.

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Liu, Wen, Benjamin H. Beck, Kedar S. Vaidya, Kevin T. Nash, Kyle P. Feeley, Scott W. Ballinger, Keke M. Pounds, et al. "Metastasis Suppressor KISS1 Seems to Reverse the Warburg Effect by Enhancing Mitochondrial Biogenesis." Cancer Research 74, no. 3 (December 18, 2013): 954–63. http://dx.doi.org/10.1158/0008-5472.can-13-1183.

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Keller, Florian, Roman Bruch, Richard Schneider, Julia Meier-Hubberten, Mathias Hafner, and Rüdiger Rudolf. "A Scaffold-Free 3-D Co-Culture Mimics the Major Features of the Reverse Warburg Effect In Vitro." Cells 9, no. 8 (August 13, 2020): 1900. http://dx.doi.org/10.3390/cells9081900.

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Most tumors consume large amounts of glucose. Concepts to explain the mechanisms that mediate the achievement of this metabolic need have proposed a switch of the tumor mass to aerobic glycolysis. Depending on whether primarily tumor or stroma cells undergo such a commutation, the terms ‘Warburg effect’ or ‘reverse Warburg effect’ were coined to describe the underlying biological phenomena. However, current in vitro systems relying on 2-D culture, single cell-type spheroids, or basal-membrane extract (BME/Matrigel)-containing 3-D structures do not thoroughly reflect these processes. Here, we aimed to establish a BME/Matrigel-free 3-D microarray cancer model to recapitulate the metabolic interplay between cancer and stromal cells that allows mechanistic analyses and drug testing. Human HT-29 colon cancer and CCD-1137Sk fibroblast cells were used in mono- and co-cultures as 2-D monolayers, spheroids, and in a cell-chip format. Metabolic patterns were studied with immunofluorescence and confocal microscopy. In chip-based co-cultures, HT-29 cells showed facilitated 3-D growth and increased levels of hexokinase-2, TP53-induced glycolysis and apoptosis regulator (TIGAR), lactate dehydrogenase, and: translocase of outer mitochondrial membrane 20 (TOMM20), when compared with HT-29 mono-cultures. Fibroblasts co-cultured with HT-29 cells expressed higher levels of mono-carboxylate transporter 4, hexokinase-2, microtubule-associated proteins 1A/1B light chain 3, and ubiquitin-binding protein p62 than in fibroblast mono-cultures, in both 2-D cultures and chips. Tetramethylrhodamin-methylester (TMRM) live-cell imaging of chip co-cultures revealed a higher mitochondrial potential in cancer cells than in fibroblasts. The findings demonstrate a crosstalk between cancer cells and fibroblasts that affects cellular growth and metabolism. Chip-based 3-D co-cultures of cancer cells and fibroblasts mimicked features of the reverse Warburg effect.

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POKORNÝ, JIŘÍ, JAN POKORNÝ, JITKA KOBILKOVÁ, ANNA JANDOVÁ, JAN VRBA, and JAN VRBA. "CANCER — PATHOLOGICAL BREAKDOWN OF COHERENT ENERGY STATES." Biophysical Reviews and Letters 09, no. 01 (March 2014): 115–33. http://dx.doi.org/10.1142/s1793048013300077.

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The fundamental property of biological systems is a coherent state far from thermodynamic equilibrium excited and sustained by energy supply. Mitochondria in eukaryotic cells produce energy and form conditions for excitation of oscillations in microtubules. Microtubule polar oscillations generate a coherent state far from thermodynamic equilibrium which makes possible cooperation of cells in the tissue. Mitochondrial dysfunction (the Warburg effect) in cancer development breaks down energy of the coherent state far from thermodynamic equilibrium and excludes the afflicted cell from the ordered multicellular tissue system. Cancer lowering of energy and coherence of the state far from thermodynamic equilibrium is the biggest difference from the healthy cells. Cancer treatment should target mitochondrial dysfunction to restore the coherent state far from thermodynamic equilibrium, apoptotic pathway, and subordination of the cell in the tissue. A vast variety of genetic changes and other disturbances in different cancers can result in several triggers of mitochondrial dysfunction. In cancers with the Warburg effect, mitochondrial dysfunction can be treated by inhibition of four isoforms of pyruvate dehydrogenase kinases. Treatment of the reverse Warburg effect cancers would be more complicated. Disturbances of cellular electromagnetic activity by conducting and asbestos fibers present a special problem of treatment.

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Pavlides, Stephanos, Diana Whitaker-Menezes, Remedios Castello-Cros, Neal Flomenberg, Agnieszka K. Witkiewicz, Philippe G. Frank, Mathew C. Casimiro, et al. "The reverse Warburg effect: Aerobic glycolysis in cancer associated fibroblasts and the tumor stroma." Cell Cycle 8, no. 23 (December 2009): 3984–4001. http://dx.doi.org/10.4161/cc.8.23.10238.

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Choi, B. W., Y. J. Jeong, S. H. Park, H. K. Oh, and S. Kang. "Reverse Warburg effect-related mitochondrial activity and 18F-FDG uptake in invasive ductal carcinoma." Annals of Oncology 30 (November 2019): ix19. http://dx.doi.org/10.1093/annonc/mdz418.015.

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Choi, Byung Wook, Young Ju Jeong, Sung Hwan Park, Hoon Kyu Oh, and Sungmin Kang. "Reverse Warburg Effect-Related Mitochondrial Activity and 18F-FDG Uptake in Invasive Ductal Carcinoma." Nuclear Medicine and Molecular Imaging 53, no. 6 (October 28, 2019): 396–405. http://dx.doi.org/10.1007/s13139-019-00613-x.

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Lee, Minjong. "Metabolic interplay between glycolysis and mitochondrial oxidation: The reverse Warburg effect and its therapeutic implication." World Journal of Biological Chemistry 6, no. 3 (2015): 148. http://dx.doi.org/10.4331/wjbc.v6.i3.148.

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Sana, Sherjeel, Maria Navas-Mareno, Z. Valey Vardney, Mark Duros, Felipe R. Lorenzo V, Katarina Kapralova, Sabina Swierczek, and Josef Prchal. "Ph-Negative Myeloproliferative Neoplasms Exhibit Some Features Of Warburg Effect." Blood 122, no. 21 (November 15, 2013): 1604. http://dx.doi.org/10.1182/blood.v122.21.1604.1604.

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Abstract Malignant cells produce energy by preferentially utilizing glycolytic pathways instead of oxidation of pyruvate in mitochondria under normal oxygen states, a metabolic alteration known as the Warburg effect. Hypoxia-inducible transcription factor 1 (HIF-1) plays a crucial role in this major shift. Some Warburg effect mediators are SLC2A1 (glucose transporter1), PDK1 (pyruvate dehydrogenase kinase, isozyme 1) and VEGF-A (vascular endothelial growth factor A). Whether the Warburg effect is exhibited by pre-malignant, clonal disorders such as Ph-negative myeloproliferative neoplasms (MPN) is not known. We investigated the presence of the Warburg effect and levels of other selected HIF-1 regulated genes in clonal granulocytes and platelets of patients with MPN, i.e. polycythemia vera (PV), essential thrombocythemia (ET), and primary or secondary myelofibrosis (MF). We collected blood samples from 21 PV, 9 ET, 9 MF patients and 14 healthy controls. Total RNA from granulocytes and platelets was isolated by Tri-Reagent and reverse transcribed using SuperScript III First-Strand Synthesis kit. Expression of HIF-1 target genes SLC2A1, PDK1, VEGF A, NFE-2 and RUNX2 was determined by qPCR using hydrolysis probes. Relative gene expression was calculated using Rest 2009 Qiagen software. We report upregulation of SLC2A1 in granulocytes and PDK1 transcripts in platelets and down regulation of PDK1 transcripts in granulocytes. HIF-1 regulated NFE-2 and RUNX1 genes transcripts were also upregulated in PV patients (see K. Kapralova abstract at this ASH meeting). The VEGF-A transcript was increased in granulocytes and platelets, and SLC2A1was increased in platelets of MPN patients, compared to controls, but this did not reach statistical significance. We then directly evaluated glucose transport in red blood cells (another feature of the Warburg effect) in some of the PV, ET and MF studied patients using Raman scattering (RS). RS is a process by which the energy of an impinging photon is shifted due to an interaction with a molecule. The energy shift of the scattered photon usually corresponds to a vibrational mode of the involved molecule. The RS spectrum is highly molecule specific, as each molecule has a distinctive set of vibrational modes. However, the RS cross-section is very small, usually requiring an enhancement mechanism. RS, as well as other optical processes like fluorescence, can be enhanced in the vicinity of metallic nanoparticles, giving rise to surface-enhanced Raman scattering (SERS) and metal-enhanced fluorescence (MEF). SERS and MEF spectroscopy measurements done on granulocytes isolated from MPN patients show that fluorescence contribution to the spectra is higher and shifted when compared to spectra from control subjects. When healthy granulocytes were incubated with various concentrations of deoxyglucose (the glucose analog not metabolized but actively transported), there was an increase of the fluorescence contribution with higher concentrations, as well as a shift in the spectrum. Together, these spectroscopic results confirm a higher glucose uptake by granulocytes from MPN patients. The increased expression of SLC2A1 and PDK1 genes and enhanced uptake of glucose in MPN patients suggest the presence of Warburg effect. The difference in regulation of transcripts of PDK1 in granulocytes and platelets may be due to tissue-specific differences of gene transcription as the HIF-1 activity is often content-specific. To validate the likely presence of the Warburg effect in MPN patients, we are now analyzing the expression of HIF-1-regulated genes in hematopoietic stem cells, as well as in reticulocytes and in the BFU-E colonies in JAK2V617Fpositive and negative MPN. Note: First and second authors contributed equally. Disclosures: Swierczek: University of Utah : No financial compensation, No financial compensation Patents & Royalties.

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Bonuccelli, Gloria, Diana Whitaker-Menezes, Remedios Castello-Cros, Stephanos Pavlides, Richard G. Pestell, Alessandro Fatatis, Agnieszka K. Witkiewicz, et al. "The reverse Warburg Effect: Glycolysis inhibitors prevent the tumor promoting effects of caveolin-1 deficient cancer associated fibroblasts." Cell Cycle 9, no. 10 (May 15, 2010): 1960–71. http://dx.doi.org/10.4161/cc.9.10.11601.

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Moir, J., J. Mann, D. Mann, and S. White. "Monocarboxylate transporter upregulation supporting the reverse warburg effect in the tumour microenvironment of pancreatic ductal adenocarcinoma." HPB 18 (April 2016): e773. http://dx.doi.org/10.1016/j.hpb.2016.01.298.

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Pokorný, Jiří, Alberto Foletti, Jitka Kobilková, Anna Jandová, Jan Vrba, Jan Vrba, Martina Nedbalová, Aleš Čoček, Andrea Danani, and Jack A. Tuszyński. "Biophysical Insights into Cancer Transformation and Treatment." Scientific World Journal 2013 (2013): 1–11. http://dx.doi.org/10.1155/2013/195028.

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Biological systems are hierarchically self-organized complex structures characterized by nonlinear interactions. Biochemical energy is transformed into work of physical forces required for various biological functions. We postulate that energy transduction depends on endogenous electrodynamic fields generated by microtubules. Microtubules and mitochondria colocalize in cells with microtubules providing tracks for mitochondrial movement. Besides energy transformation, mitochondria form a spatially distributed proton charge layer and a resultant strong static electric field, which causes water ordering in the surrounding cytosol. These effects create conditions for generation of coherent electrodynamic field. The metabolic energy transduction pathways are strongly affected in cancers. Mitochondrial dysfunction in cancer cells (Warburg effect) or in fibroblasts associated with cancer cells (reverse Warburg effect) results in decreased or increased power of the generated electromagnetic field, respectively, and shifted and rebuilt frequency spectra. Disturbed electrodynamic interaction forces between cancer and healthy cells may favor local invasion and metastasis. A therapeutic strategy of targeting dysfunctional mitochondria for restoration of their physiological functions makes it possible to switch on the natural apoptotic pathway blocked in cancer transformed cells. Experience with dichloroacetate in cancer treatment and reestablishment of the healthy state may help in the development of novel effective drugs aimed at the mitochondrial function.

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Schiliro, Chelsea, and Bonnie L. Firestein. "Mechanisms of Metabolic Reprogramming in Cancer Cells Supporting Enhanced Growth and Proliferation." Cells 10, no. 5 (April 29, 2021): 1056. http://dx.doi.org/10.3390/cells10051056.

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Cancer cells alter metabolic processes to sustain their characteristic uncontrolled growth and proliferation. These metabolic alterations include (1) a shift from oxidative phosphorylation to aerobic glycolysis to support the increased need for ATP, (2) increased glutaminolysis for NADPH regeneration, (3) altered flux through the pentose phosphate pathway and the tricarboxylic acid cycle for macromolecule generation, (4) increased lipid uptake, lipogenesis, and cholesterol synthesis, (5) upregulation of one-carbon metabolism for the production of ATP, NADH/NADPH, nucleotides, and glutathione, (6) altered amino acid metabolism, (7) metabolism-based regulation of apoptosis, and (8) the utilization of alternative substrates, such as lactate and acetate. Altered metabolic flux in cancer is controlled by tumor-host cell interactions, key oncogenes, tumor suppressors, and other regulatory molecules, including non-coding RNAs. Changes to metabolic pathways in cancer are dynamic, exhibit plasticity, and are often dependent on the type of tumor and the tumor microenvironment, leading in a shift of thought from the Warburg Effect and the “reverse Warburg Effect” to metabolic plasticity. Understanding the complex nature of altered flux through these multiple pathways in cancer cells can support the development of new therapies.

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Duda, Przemysław, Jakub Janczara, James A. McCubrey, Agnieszka Gizak, and Dariusz Rakus. "The Reverse Warburg Effect Is Associated with Fbp2-Dependent Hif1α Regulation in Cancer Cells Stimulated by Fibroblasts." Cells 9, no. 1 (January 14, 2020): 205. http://dx.doi.org/10.3390/cells9010205.

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Fibroblasts are important contributors to cancer development. They create a tumor microenvironment and modulate our metabolism and treatment resistance. In the present paper, we demonstrate that healthy fibroblasts induce metabolic coupling with non-small cell lung cancer cells by down-regulating the expression of glycolytic enzymes in cancer cells and increasing the fibroblasts’ ability to release lactate and thus support cancer cells with energy-rich glucose-derived metabolites, such as lactate and pyruvate—a process known as the reverse Warburg effect. We demonstrate that these changes result from a fibroblasts-stimulated increase in the expression of fructose bisphosphatase (Fbp) in cancer cells and the consequent modulation of Hif1α function. We show that, in contrast to current beliefs, in lung cancer cells, the predominant and strong interaction with the Hif1α form of Fbp is not the liver (Fbp1) but in the muscle (Fbp2) isoform. Since Fbp2 oligomerization state and thus, its role is regulated by AMP and NAD+—crucial indicators of cellular metabolic conditions—we hypothesize that the Hif1α-dependent regulation of the metabolism in cancer is modulated through Fbp2, a sensor of the energy and redox state of a cell.

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Martinez-Outschoorn, Ubaldo E., Diana Whitaker-Menezes, Matias Valsecchi, Maria P. Martinez-Cantarin, Alina Dulau-Florea, Jerald Gong, Anthony Howell, et al. "Reverse Warburg Effect in a Patient With Aggressive B-Cell Lymphoma: Is Lactic Acidosis a Paraneoplastic Syndrome?" Seminars in Oncology 40, no. 4 (August 2013): 403–18. http://dx.doi.org/10.1053/j.seminoncol.2013.04.016.

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Wilde, Lindsay, Megan Roche, Marina Domingo-Vidal, Katherina Tanson, Nancy Philp, Joseph Curry, and Ubaldo Martinez-Outschoorn. "Metabolic coupling and the Reverse Warburg Effect in cancer: Implications for novel biomarker and anticancer agent development." Seminars in Oncology 44, no. 3 (June 2017): 198–203. http://dx.doi.org/10.1053/j.seminoncol.2017.10.004.

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Furlanello, Sara, Andrea Padoan, Thomas Brefort, Thomas Laufer, Carlo-Federico Zambon, Filippo Navaglia, Stefania Moz, Dania Bozzato, Giorgio Arrigoni, and Daniela Basso. "SMAD4 related transfer through exosomes of glycolytic enzymes and miR-1260a underlies the reverse Warburg effect in PDAC." Pancreatology 17, no. 3 (July 2017): S7. http://dx.doi.org/10.1016/j.pan.2017.05.022.

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Manley, Sharon J., Wen Liu, and Danny R. Welch. "The KISS1 metastasis suppressor appears to reverse the Warburg effect by shifting from glycolysis to mitochondrial beta-oxidation." Journal of Molecular Medicine 95, no. 9 (June 8, 2017): 951–63. http://dx.doi.org/10.1007/s00109-017-1552-2.

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Li, Na, and Xianquan Zhan. "Multiomics-based energy metabolism heterogeneity and its regulation by antiparasite drug ivermectin." Journal of Clinical Oncology 38, no. 15_suppl (May 20, 2020): e18080-e18080. http://dx.doi.org/10.1200/jco.2020.38.15_suppl.e18080.

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e18080 Background: Energy metabolism heterogeneity is a hallmark in ovarian cancer, namely the Warburg effect and the reverse Warburg effects coexist in ovarian cancer. Exploration of energy metabolism heterogeneity benefits for discovery of the effective biomarkers for ovarian cancers. Methods: Comprehensive analysis of mitochondrial proteomics data (1198 mitochondrial differentially expressed proteins), mitochondrial phosphorpoteomics data (67 mitochondrial phosphorproteins), proteomics data (205 differentially expressed proteins), and transcriptomics data (20115 genes in 419 ovarian cancer samples) was useful. Results: It revealed (i) the upregulations of rate-limiting enzymes PKM2 in glycolysis, IDH2 in Kreb’s cycle, and UQCRH in oxidative phosphorylation (OXPHOS) pathways, (ii) the upregulation of PDHB that converts pyruvate from glycolysis into acetyl-CoA in Kreb’s cycle. Anti-parasite drug ivermectin demonstrated its strong abilities to inhibit proliferation and cell cycle progression and promote apoptosis in EOC cells, through molecular networks to target PFKP in glycolysis, IDH2 and IDH3B in Kreb’s cycle, ND2, ND5, CYTB, and UQCRH in OXPHOS, and MCT1 and MCT4 in lactate shuttle to inhibit EOC growth. Those results were further confirmed in the ovarian cancer cell models and tissues. Conclusions: It clearly concluded that ivermectin might have new potential for ovarian cancer treatment through regulating energy metabolism pathways. These findings provide more accurate understanding of molecular mechanisms of ovarian cancers and discovery of effective energy-metabolism-heterogeneity-based therapeutic drugs for ovarian cancers.

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Parkinson, E. Kenneth, Jerzy Adamski, Grit Zahn, Andreas Gaumann, Fabian Flores-Borja, Christine Ziegler, and Maria E. Mycielska. "Extracellular citrate and metabolic adaptations of cancer cells." Cancer and Metastasis Reviews 40, no. 4 (December 2021): 1073–91. http://dx.doi.org/10.1007/s10555-021-10007-1.

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Abstract It is well established that cancer cells acquire energy via the Warburg effect and oxidative phosphorylation. Citrate is considered to play a crucial role in cancer metabolism by virtue of its production in the reverse Krebs cycle from glutamine. Here, we review the evidence that extracellular citrate is one of the key metabolites of the metabolic pathways present in cancer cells. We review the different mechanisms by which pathways involved in keeping redox balance respond to the need of intracellular citrate synthesis under different extracellular metabolic conditions. In this context, we further discuss the hypothesis that extracellular citrate plays a role in switching between oxidative phosphorylation and the Warburg effect while citrate uptake enhances metastatic activities and therapy resistance. We also present the possibility that organs rich in citrate such as the liver, brain and bones might form a perfect niche for the secondary tumour growth and improve survival of colonising cancer cells. Consistently, metabolic support provided by cancer-associated and senescent cells is also discussed. Finally, we highlight evidence on the role of citrate on immune cells and its potential to modulate the biological functions of pro- and anti-tumour immune cells in the tumour microenvironment. Collectively, we review intriguing evidence supporting the potential role of extracellular citrate in the regulation of the overall cancer metabolism and metastatic activity.

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Maués, Tábata, Táya Figueiredo de Oliveira, Kênia Balbi El-Jaick, Agnes Marie Sá Figueiredo, Maria De Lourdes Gonçalves Ferreira, and Ana Maria Reis Ferreira. "PGAM1 and TP53 mRNA levels in canine mammary carcinomas – Short communication." Acta Veterinaria Hungarica 69, no. 1 (June 5, 2021): 50–54. http://dx.doi.org/10.1556/004.2021.00008.

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AbstractTP53 and PGAM1 genes play a key role in glycolysis which is an essential metabolic pathway of cancer cells for obtaining energy. The purpose of this work was to evaluate PGAM1 and TP53 mRNA expressions in canine mammary carcinomas (CMC) and to correlate them with animal data and tumour histological features. None of the nine samples analysed revealed PGAM1 DNA sequence variations. PGAM1 and TP53 RNA expressions from 21 CMC were analysed using a one-step reverse transcription-PCR kit and its platform system. Most CMC samples had low levels of PGAM1 mRNA (71.5%) and normal expression of TP53 mRNA (95.2%). Our results suggest a different feature of the Warburg effect on canine mammary cancer cells compared to human cells.

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Köpnick, Anna-Lena, Annika Jansen, Katharina Geistlinger, Nathan Hugo Epalle, and Eric Beitz. "Basigin drives intracellular accumulation of l-lactate by harvesting protons and substrate anions." PLOS ONE 16, no. 3 (March 26, 2021): e0249110. http://dx.doi.org/10.1371/journal.pone.0249110.

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Transmembrane transport of l-lactate by members of the monocarboxylate transporter family, MCT, is vital in human physiology and a malignancy factor in cancer. Interaction with an accessory protein, typically basigin, is required to deliver the MCT to the plasma membrane. It is unknown whether basigin additionally exerts direct effects on the transmembrane l-lactate transport of MCT1. Here, we show that the presence of basigin leads to an intracellular accumulation of l-lactate 4.5-fold above the substrate/proton concentrations provided by the external buffer. Using basigin truncations we localized the effect to arise from the extracellular Ig-I domain. Identification of surface patches of condensed opposite electrostatic potential, and experimental analysis of charge-affecting Ig-I mutants indicated a bivalent harvesting antenna functionality for both, protons and substrate anions. From these data, and determinations of the cytosolic pH with a fluorescent probe, we conclude that the basigin Ig-I domain drives lactate uptake by locally increasing the proton and substrate concentration at the extracellular MCT entry site. The biophysical properties are physiologically relevant as cell growth on lactate media was strongly promoted in the presence of the Ig-I domain. Lack of the domain due to shedding, or misfolding due to breakage of a stabilizing disulfide bridge reversed the effect. Tumor progression according to classical or reverse Warburg effects depends on the transmembrane l-lactate distribution, and this study shows that the basigin Ig-I domain is a pivotal determinant.

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Reiter, Russel J., Ramaswamy Sharma, Qiang Ma, Sergio Rosales-Corral, Dario Acuna-Castroviejo, and Germaine Escames. "Inhibition of mitochondrial pyruvate dehydrogenase kinase: a proposed mechanism by which melatonin causes cancer cells to overcome cytosolic glycolysis, reduce tumor biomass and reverse insensitivity to chemotherapy." Melatonin Research 2, no. 3 (August 31, 2019): 105–19. http://dx.doi.org/10.32794/mr11250033.

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This review presents a hypothesis to explain the role of melatonin in regulating glucose metabolism in cancer cells. Many cancer cells use cytosolic glycolysis (the Warburg effect) to produce energy (ATP). Under these conditions, glucose is primarily converted to lactate which is released into the blood in large quantities. The Warburg effect gives cancer cells advantages in terms of enhanced macromolecule synthesis required for accelerated cellular proliferation, reduced cellular apoptosis which enhances tumor biomass and a greater likelihood of metastasis. Based on available data, high circulating melatonin levels at night serve as a signal for breast cancer cells to switch from cytosolic glycolysis to mitochondrial glucose oxidation and oxidative phosphorylation for ATP production. In this situation, melatonin promotes the synthesis of acetyl-CoA from pyruvate; we speculate that melatonin does this by inhibiting the mitochondrial enzyme pyruvate dehydrogenase kinase (PDK) which normally inhibits pyruvate dehydrogenase complex (PDC), the enzyme that controls the pyruvate to acetyl-CoA conversion. Acetyl-CoA has several important functions in the mitochondria; it feeds into the citric acid cycle which improves oxidative phosphorylation and, additionally, it is a necessary co-factor for the rate limiting enzyme, arylalkylamine N-acetyltransferase, in mitochondrial melatonin synthesis. When breast cancer cells are using cytosolic glycolysis (during the day) they are of the cancer phenotype; at night when they are using mitochondria to produce ATP via oxidative phosphorylation, they have a normal cell phenotype. If this day:night difference in tumor cell metabolism is common in other cancers, it indicates that these tumor cells are only cancerous part of the time. We also speculate that high nighttime melatonin levels also reverse the insensitivity of tumors to chemotherapy.

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Fu, Yaojie, Shanshan Liu, Shanghelin Yin, Weihong Niu, Wei Xiong, Ming Tan, Guiyuan Li, and Ming Zhou. "The reverse Warburg effect is likely to be an Achilles' heel of cancer that can be exploited for cancer therapy." Oncotarget 8, no. 34 (May 25, 2017): 57813–25. http://dx.doi.org/10.18632/oncotarget.18175.

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Zhang, G., J. Li, X. Wang, Y. Ma, X. Yin, F. Wang, H. Zheng, X. Duan, G. C. Postel, and X. F. Li. "The Reverse Warburg Effect and 18F-FDG Uptake in Non-Small Cell Lung Cancer A549 in Mice: A Pilot Study." Journal of Nuclear Medicine 56, no. 4 (February 26, 2015): 607–12. http://dx.doi.org/10.2967/jnumed.114.148254.

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Ordway, Bryce, Michal Tomaszewski, Samantha Byrne, Dominique Abrahams, Pawel Swietach, Robert J. Gillies, and Mehdi Damaghi. "Targeting of Evolutionarily Acquired Cancer Cell Phenotype by Exploiting pHi-Metabolic Vulnerabilities." Cancers 13, no. 1 (December 28, 2020): 64. http://dx.doi.org/10.3390/cancers13010064.

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Evolutionary dynamics can be used to control cancers when a cure is not clinically considered to be achievable. Understanding Darwinian intratumoral interactions of microenvironmental selection forces can be used to steer tumor progression towards a less invasive trajectory. Here, we approach intratumoral heterogeneity and evolution as a dynamic interaction among subpopulations through the application of small, but selective biological forces such as intracellular pH (pHi) and/or extracellular pH (pHe) vulnerabilities. Increased glycolysis is a prominent phenotype of cancer cells under hypoxia or normoxia (Warburg effect). Glycolysis leads to an important aspect of cancer metabolism: reduced pHe and higher pHi. We recently showed that decreasing pHi and targeting pHi sensitive enzymes can reverse the Warburg effect (WE) phenotype and inhibit tumor progression. Herein, we used diclofenac (DIC) repurposed to control MCT activity, and Koningic acid (KA) that is a GAPDH partial inhibitor, and observed that we can control the subpopulation of cancer cells with WE phenotype within a tumor in favor of a less aggressive phenotype without a WE to control progression and metastasis. In a 3D spheroid co-cultures, we showed that our strategy can control the growth of more aggressive MDA-MB-231 cells, while sparing the less aggressive MCF7 cells. In an animal model, we show that our approach can reduce tumor growth and metastasis. We thus propose that evolutionary dynamics can be used to control tumor cells’ clonal or sub-clonal populations in favor of slower growth and less damage to patients. We propose that this can result in cancer control for tumors where cure is not an option.

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El-Sayed, Nahed N. E., Taghreed M. Al-Otaibi, Mona Alonazi, Vijay H. Masand, Assem Barakat, Zainab M. Almarhoon, and Abir Ben Bacha. "Synthesis and Characterization of Some New Quinoxalin-2(1H)one and 2-Methyl-3H-quinazolin-4-one Derivatives Targeting the Onset and Progression of CRC with SRA, Molecular Docking, and ADMET Analyses." Molecules 26, no. 11 (May 23, 2021): 3121. http://dx.doi.org/10.3390/molecules26113121.

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The pathogenesis of colorectal cancer is a multifactorial process. Dysbiosis and the overexpression of COX-2 and LDHA are important effectors in the initiation and development of the disease through chromosomal instability, PGE2 biosynthesis, and induction of the Warburg effect, respectively. Herein, we report the in vitro testing of some new quinoxalinone and quinazolinone Schiff’s bases as: antibacterial, COX-2 and LDHA inhibitors, and anticolorectal agents on HCT-116 and LoVo cells. Moreover, molecular docking and SAR analyses were performed to identify the structural features contributing to the biological activities. Among the synthesized molecules, the most active cytotoxic agent, (6d) was also a COX-2 inhibitor. In silico ADMET studies predicted that (6d) would have high Caco-2 permeability, and %HIA (99.58%), with low BBB permeability, zero hepatotoxicity, and zero risk of sudden cardiac arrest, or mutagenicity. Further, (6d) is not a potential P-gp substrate, instead, it is a possible P-gpI and II inhibitor, therefore, it can prevent or reverse the multidrug resistance of the anticancer drugs. Collectively, (6d) can be considered as a promising lead suitable for further optimization to develop anti-CRC agents or glycoproteins inhibitors.

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Pavlides, Stephanos, Aristotelis Tsirigos, Iset Vera, Neal Flomenberg, Philippe G. Frank, Mathew C. Casimiro, Chenguang Wang, et al. "Transcriptional evidence for the "Reverse Warburg Effect" in human breast cancer tumor stroma and metastasis: Similarities with oxidative stress, inflammation, Alzheimer's disease, and "Neuron-Glia Metabolic Coupling"." Aging 2, no. 4 (March 31, 2010): 185–99. http://dx.doi.org/10.18632/aging.100134.

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Peng, Bo, Si-Yuan Zhang, Ka Iong Chan, Zhang-Feng Zhong, and Yi-Tao Wang. "Novel Anti-Cancer Products Targeting AMPK: Natural Herbal Medicine against Breast Cancer." Molecules 28, no. 2 (January 11, 2023): 740. http://dx.doi.org/10.3390/molecules28020740.

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Breast cancer is a common cancer in women worldwide. The existing clinical treatment strategies have been able to limit the progression of breast cancer and cancer metastasis, but abnormal metabolism, immunosuppression, and multidrug resistance involving multiple regulators remain the major challenges for the treatment of breast cancer. Adenosine 5′-monophosphate (AMP)-Activated Protein Kinase (AMPK) can regulate metabolic reprogramming and reverse the “Warburg effect” via multiple metabolic signaling pathways in breast cancer. Previous studies suggest that the activation of AMPK suppresses the growth and metastasis of breast cancer cells, as well as stimulating the responses of immune cells. However, some other reports claim that the development and poor prognosis of breast cancer are related to the overexpression and aberrant activation of AMPK. Thus, the role of AMPK in the progression of breast cancer is still controversial. In this review, we summarize the current understanding of AMPK, particularly the comprehensive bidirectional functions of AMPK in cancer progression; discuss the pharmacological activators of AMPK and some specific molecules, including the natural products (including berberine, curcumin, (−)-epigallocatechin-3-gallate, ginsenosides, and paclitaxel) that influence the efficacy of these activators in cancer therapy; and elaborate the role of AMPK as a potential therapeutic target for the treatment of breast cancer.

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Harrison, Mark A. A., Emily M. Hochreiner, Brooke P. Benjamin, Sean E. Lawler, and Kevin J. Zwezdaryk. "Metabolic Reprogramming of Glioblastoma Cells during HCMV Infection Induces Secretome-Mediated Paracrine Effects in the Microenvironment." Viruses 14, no. 1 (January 7, 2022): 103. http://dx.doi.org/10.3390/v14010103.

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Glioblastoma (GBM) is an aggressive primary central nervous system neoplasia with limited therapeutic options and poor prognosis. Following reports of cytomegalovirus (HCMV) in GBM tumors, the anti-viral drug Valganciclovir was administered and found to significantly increase the longevity of GBM patients. While these findings suggest a role for HCMV in GBM, the relationship between them is not clear and remains controversial. Treatment with anti-viral drugs may prove clinically useful; however, their results do not explain the underlying mechanism between HCMV infection and GBM progression. We hypothesized that HCMV infection would metabolically reprogram GBM cells and that these changes would allow for increased tumor progression. We infected LN-18 GBM cells and employed a Seahorse Bioanalyzer to characterize cellular metabolism. Increased mitochondrial respiration and glycolytic rates were observed following infection. These changes were accompanied by elevated production of reactive oxygen species and lactate. Due to lactate’s numerous tumor-promoting effects, we examined the impact of paracrine signaling of HCMV-infected GBM cells on uninfected stromal cells. Our results indicated that, independent of viral transmission, the secretome of HCMV-infected GBM cells was able to alter the expression of key metabolic proteins and epigenetic markers. This suggests a mechanism of action where reprogramming of GBM cells alters the surrounding tumor microenvironment to be permissive to tumor progression in a manner akin to the Reverse-Warburg Effect. Overall, this suggests a potential oncomodulatory role for HCMV in the context of GBM.

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Aghakhani, Sahar, Sylvain Soliman, and Anna Niarakis. "Metabolic reprogramming in Rheumatoid Arthritis Synovial Fibroblasts: A hybrid modeling approach." PLOS Computational Biology 18, no. 12 (December 12, 2022): e1010408. http://dx.doi.org/10.1371/journal.pcbi.1010408.

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Rheumatoid Arthritis (RA) is an autoimmune disease characterized by a highly invasive pannus formation consisting mainly of Synovial Fibroblasts (RASFs). This pannus leads to cartilage, bone, and soft tissue destruction in the affected joint. RASFs’ activation is associated with metabolic alterations resulting from dysregulation of extracellular signals’ transduction and gene regulation. Deciphering the intricate mechanisms at the origin of this metabolic reprogramming may provide sign insight into RASFs’ involvement in RA’s pathogenesis and offer new therapeutic strategies. Qualitative and quantitative dynamic modeling can address some of these features, but hybrid models represent a real asset in their ability to span multiple layers of biological machinery. This work presents the first hybrid RASF model: the combination of a cell-specific qualitative regulatory network with a global metabolic network. The automated framework for hybrid modeling exploits the regulatory network’s trap-spaces as additional constraints on the metabolic network. Subsequent flux balance analysis allows assessment of RASFs’ regulatory outcomes’ impact on their metabolic flux distribution. The hybrid RASF model reproduces the experimentally observed metabolic reprogramming induced by signaling and gene regulation in RASFs. Simulations also enable further hypotheses on the potential reverse Warburg effect in RA. RASFs may undergo metabolic reprogramming to turn into "metabolic factories", producing high levels of energy-rich fuels and nutrients for neighboring demanding cells through the crucial role of HIF1.

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Pavlides, Stephanos, Aristotelis Tsirigos, Iset Vera, Neal Flomenberg, Philippe G. Frank, Mathew C. Casimiro, Chenguang Wang, et al. "Loss of stromal caveolin-1 leads to oxidative stress, mimics hypoxia and drives inflammation in the tumor microenvironment, conferring the “reverse Warburg effect”: A transcriptional informatics analysis with validation." Cell Cycle 9, no. 11 (June 2010): 2201–19. http://dx.doi.org/10.4161/cc.9.11.11848.

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Pfeilstocker, Michael, Peter Wihlidal, Franz Varga, Elisabeth Pittermann, and Heidrun Karlic. "Imatinib Mesylate Induced Reversal of Leukemic Gene Phenotype in HL60 Cells Coincides with Stimulation of Oxidative Metabolism." Blood 110, no. 11 (November 16, 2007): 4190. http://dx.doi.org/10.1182/blood.v110.11.4190.4190.

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Abstract Besides blockade of tyrosine kinases such as c-kit, Imatinib mesylate (IM) regulates glucose flux through downregulation of GLUT-1 transporters in human leukemia cells. This mechanism has the potential to induce regression of type 2 diabetes and hyperlipidemia as observed in patients with chronic myeloid leukemia or hypereosinophilic syndrome. In addition, there is a stimulatory effect of IM on differentiation of human mesenchymal stem cells. Its synergism with retinoic acid or low dose Ara-C is applied in treatment of acute myeloid leukemia (AML). Thus, the AML-derived c-kit positive cell line HL60 was chosen for studying the effect of IM on expression of genes associated with differentiation and metabolism. We analysed the possible feedback on transcription factors (AML1 and AML3) and consequences regarding differentiation and metabolism - associated genes. Quantitative reverse transcriptase PCR analyses revealed that IM treatment of HL60 cells downregulates mRNA synthesis of AML1 and AML3 by 70% without affecting transcription of the c-abl tyrosine kinase. IM reduces expression of CD34 mRNA from 20% to 6% of the housekeeping gene G6PD. The appearance of differentiated cells was accompanied by a remarkable stimulation of mRNAs from CD11b and CD14 (monocyte markers) reaching 4-fold higher expression levels relative to G6PD. This was associated with an increased proportion of osteocalcin (OCN), which has recently been shown to enhance mitochondrial activity. A 2-fold stimulation of a fat-metabolism associated mitochondrial palmitoyltransferase (CPT1B) and 10-fold stimulation of microsomal carnitine palmitoyltransferase and the carnitine transporter OCTN2 supports previous data indicating an IM-associated stimulation of oxidative metabolism resulting in a regression of type-2 diabetes and hyperlipidemia. Our current investigations show that IM-associated attenuation of cell proliferation inhibited transcription factors AML1 and AML3 and triggered differentiation in the leukemic cell line HL60, as reflected by altered mRNA expression of surface marker genes. The IM - induced stimulation of lipid metabolism in HL60 confirms previous data indicating a reversal of the Warburg effect in K562 cells without cytocidal activity. This indicates a similar mechanism as known for other drugs and strategies targeting glucose or fat metabolism, which are discussed in the context of cancer prevention and treatment.

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Huang, Kangyu, Bingqing Tang, Zihong Cai, Xianjun He, Qiuli Li, Nannan Liu, Dainan Lin, et al. "HDACi Targets IKZF1 Deletion High-Risk Acute Lymphoblastic Leukemia By Inducing IKZF1 Expression and Rescuing IKZF1 Function in Vitro and In Vivo." Blood 138, Supplement 1 (November 5, 2021): 514. http://dx.doi.org/10.1182/blood-2021-152926.

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Abstract The IKZF1 gene codes the transcription factor IKAROS with key regulatory functions in lymphopoiesis. Recurrent focal IKZF1 deletions (IKZF1 del), which affects the coding regions of IKZF1, have been identified as poor outcome in 30-40% adult B-ALL. Loss of IKAROS confer stem cell-like phenotype, upregulation of self-renewal capacity and cell-adhesion molecules, and TKI resistance. However, there are not specifically therapeutic options for IKZF1 del ALL and current protocols could not abrogate the adverse effect of IKZF1 del.Considering that IKAROS acts as a key component of the nucleosome remodeling and deacetylation (NuRD) complex engaging in development and metabolism, we speculate that epigenetic drugs, such as HDACi, might play a potent role in IKZF1 del high-risk B-ALL. Firstly, B-ALL cell lines (IKZF1 del: MUTZ-5, MHH-CALL-4; IKZF1 wt: NALM6) and primary patient samples (n=10, 5 with IKZF1 del and 5 with IKZF1 wt) were treated with different HDACi, including valproic acid, vorinostat, romidepsin, RGFP966 and a novel HDAC-selective inhibitor tucidinostat. But noteworthily, only tucidinostat yielded specific and selective proliferation inhibition in IKZF1 del cell line(IC 50=1.377±0.05) and IKZF1 del patients samples (IC 50=2.318±0.07), compared with the effect on IKZF1 wt cells. Interestingly, tucidinostat induced remarked increase of mRNA and protein of IKZF1 expression in leukemia bulk and IKZF1 del single cell. Seahorse metabolic flux assay, lactate and ATP measurements was performed and revealed that tucidinostat treatment reduced glycolysis (P=0.0067), lactic acid (P＜0.0001) and ATP level (P＜0.0001) in IKZF1 del B-ALL cell lines. To verify metabolic change is depend on IKZF1 induction or not,dominant-negative Ikaros isoform 6 (DN-IK6), deletion of exons 4-7, was transfected into IKZF1 wt Nalm-6 cell line to negative regulate of IKZF1 wide-type expression. Overexpression of DN-IK6 in Nalm-6, increases sensitivity to tucidinostat, glycolytic capacity(p=0.05) and glycolytic reserve (p=0.012) also increases. While tucidinostat treating with the IK6-Nalm-6, tucidinostat would restore the transcriptional repressor function of the remaining wild-type IKZF1 allele and decrease glycolytic capacity(p=0.011) and glycolytic reserve(p=0.014). Notably, the metabolic rate-limiting enzymes HK2 and PKM2 were strongly repressed. These data indicate that tucidinostat reverses the metabolic reprogramming of glycolysis or Warburg effect in IKZF1 del B-ALL in an IKZF1-inducing dependent manner. For in vivo study, PDX model with immunodeficient NOD/SCID/IL2Rgnull mice were injected with heavily-treated refractory/relapsed IKZF1 del B-ALL patient samples (n=2) and treated with tucidinostat with different dosage of 5-12.5mg/kg/day. Administration of tucidinostat observed IKAROS expression trajectory and resulted in prolonged animal survival in IKZF1 del B-ALL PDX model（P＜0.0001). Secondary transplantation of ALL cells from tucidinostat or vehicle-treated (1 x10 6) recipients revealed significantly improved survival in tucidinostat -treated group (p= 0.0235). These results indicate that tucidinostat treatment might elimination leukemia-initiating cells.Additionally, to profile the IKZF1 del B-ALL chromatin accessibility changes after tucidinostat-treatment. We performed ATAC-seq and observed a clear increase in accessibility at TCA cycle related gene and decrease in accessibility at glycolysis related gene.Furthermore, tucidinostat, formerly known as chidamide, was added to an open-label, one-arm PDT-Ph-like-ALL trial targeting adult Ph-like ALL, which is characterized with high frequency in IKZF1 deletions (Clinicaltrials.gov. NCT03564470). Preliminary data of PDT-Ph-like-ALL indicate that tucidinostat was effective and well-tolerated, yielded promising response in IKZF1 del Ph-like ALL (ASH2018, poster 4011; EHA 2019, PF181). Collectively, our study demonstrates that the novel HDAC-selective inhibitor, tucidinostat, could specifically target IKZF1 del high-risk B-ALL, by restoring the IKZF1 expression, resulting in attenuation of proliferation, reverse the Warburg effect and improvement of the survival in PDX model and preliminary data in clinical trial. These findings provide mechanistic insights and a promising therapeutic strategy for IKZF1 haploinsufficiency alterations B-ALL patients. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

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Cheng, Yao, Zhenchuan Ma, Shiyuan Liu, Xiaoping Yang, and Shaomin Li. "CircLPAR3 knockdown suppresses esophageal squamous cell carcinoma cell oncogenic phenotypes and Warburg effect through miR-873-5p/LDHA axis." Human & Experimental Toxicology 41 (January 2022): 096032712211436. http://dx.doi.org/10.1177/09603271221143695.

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Background Circular RNAs (circRNAs) have been identified to participate in regulating multiple malignancies. Herein, this study aimed to explore the clinical significance, biological function, and regulatory mechanisms of circRNA lysophosphatidic acid receptor 3 (circLPAR3) in esophageal squamous cell carcinoma (ESCC) cell malignant phenotypes and Warburg effect. Methods The qRT-PCR and Western blot were used to detect the levels of genes and proteins. Glucose uptake and lactate production were detected to determine the Warburg effect. The effects of circLPAR3 on ESCC cell proliferation, apoptosis, and metastasis were evaluated by MTT, 5-ethynyl-2′-deoxyuridine (EdU), flow cytometry, wound healing, and transwell assays. The binding interaction between miR-873-5p and circLPAR3 or lactate dehydrogenase A (LDHA) was verified using dual-luciferase reporter and RIP assays. Xenograft mice models were established to conduct in vivo analysis. Results CircLPAR3 is a stable circRNA and was increased in ESCC tissues and cells. Functionally, circLPAR3 knockdown suppressed ESCC cell Warburg effect, proliferation, metastasis, and induced apoptosis in vitro, and impeded xenograft tumor growth and Warburg effect in ESCC mice models. Mechanistically, circLPAR3 served as a sponge for miR-873-5p, which targeted LDHA. Moreover, circLPAR3 could regulate LDHA expression by sponging miR-873-5p. Thereafter, rescue experiments suggested that miR-873-5p inhibition reversed the anticancer effects of circLPAR3 silencing on ESCC cells. Furthermore, miR-873-5p overexpression restrained ESCC cell Warburg effect and oncogenic phenotypes, which were abolished by LDHA up-regulation. Conclusion CircLPAR3 knockdown suppressed ESCC cell growth, metastasis, and Warburg effect by miR-873-5p/LDHA axis, implying a promising molecular target for ESCC therapy.

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Sandforth, Leontine, Nourhane Ammar, Lisa Antonia Dinges, Christoph Röcken, Alexander Arlt, Susanne Sebens, and Heiner Schäfer. "Impact of the Monocarboxylate Transporter-1 (MCT1)-Mediated Cellular Import of Lactate on Stemness Properties of Human Pancreatic Adenocarcinoma Cells." Cancers 12, no. 3 (March 3, 2020): 581. http://dx.doi.org/10.3390/cancers12030581.

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Metabolite exchange between stromal and tumor cells or among tumor cells themselves accompanies metabolic reprogramming in cancer including pancreatic adenocarcinoma (PDAC). Some tumor cells import and utilize lactate for oxidative energy production (reverse Warburg-metabolism) and the presence of these “reverse Warburg“ cells associates with a more aggressive phenotype and worse prognosis, though the underlying mechanisms are poorly understood. We now show that PDAC cells (BxPc3, A818-6, T3M4) expressing the lactate-importer monocarboxylate transporter-1 (MCT1) are protected by lactate against gemcitabine-induced apoptosis in a MCT1-dependent fashion, contrary to MCT1-negative PDAC cells (Panc1, Capan2). Moreover, lactate administration under glucose starvation, resembling reverse Warburg co a phenotype of BxPc3 and T3M4 cells that confers greater potential of clonal growth upon re-exposure to glucose, along with drug resistance and elevated expression of the stemness marker Nestin and reprogramming factors (Oct4, KLF4, Nanog). These lactate dependent effects on stemness properties are abrogated by the MCT1/lactate-uptake inhibitor 7ACC2 or MCT1 knock-down. Furthermore, the clinical relevance of these observations was supported by detecting co-expression of MCT1 and reprogramming factors in human PDAC tissues. In conclusion, the MCT1-dependent import of lactate supplies “reverse Warburg “PDAC cells with an efficient driver of metabostemness. This condition may essentially contribute to malignant traits including therapy resistance.

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Yang, Ronghua, and Caihong Guo. "Discovery of potent pyruvate dehydrogenase kinase inhibitors and evaluation of their anti-lung cancer activity under hypoxia." MedChemComm 9, no. 11 (2018): 1843–49. http://dx.doi.org/10.1039/c8md00453f.

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Kaiser, Alexander, Thomas Krüger, Gabriele Eiselt, Joachim Bechler, Olaf Kniemeyer, Otmar Huber, and Martin Schmidt. "Identification of PARP-1, Histone H1 and SIRT-1 as New Regulators of Breast Cancer-Related Aromatase Promoter I.3/II." Cells 9, no. 2 (February 12, 2020): 427. http://dx.doi.org/10.3390/cells9020427.

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Paracrine interactions between malignant estrogen receptor positive (ER+) breast cancer cells and breast adipose fibroblasts (BAFs) stimulate estrogen biosynthesis by aromatase in BAFs. In breast cancer, mainly the cAMP-responsive promoter I.3/II-region mediates excessive aromatase expression. A rare single nucleotide variant (SNV) in this promoter region, which caused 70% reduction in promoter activity, was utilized for the identification of novel regulators of aromatase expression. To this end, normal and mutant promoter activities were measured in luciferase reporter gene assays. DNA-binding proteins were captured by DNA-affinity and identified by mass spectrometry. The DNA binding of proteins was analyzed using electrophoretic mobility shift assays, immunoprecipitation-based in vitro binding assays and by chromatin immunoprecipitation in BAFs in vivo. Protein expression and parylation were analyzed by western blotting. Aromatase activities and RNA-expression were measured in BAFs. Functional consequences of poly (ADP-ribose) polymerase-1 (PARP-1) knock-out, rescue or overexpression, respectively, were analyzed in murine embryonic fibroblasts (MEFs) and the 3T3-L1 cell model. In summary, PARP-1 and histone H1 (H1) were identified as critical regulators of aromatase expression. PARP-1-binding to the SNV-region was crucial for aromatase promoter activation. PARP-1 parylated H1 and competed with H1 for DNA-binding, thereby inhibiting its gene silencing action. In MEFs (PARP-1 knock-out and wild-type) and BAFs, PARP-1-mediated induction of the aromatase promoter showed bi-phasic dose responses in overexpression and inhibitor experiments, respectively. The HDAC-inhibitors butyrate, panobinostat and selisistat enhanced promoter I.3/II-mediated gene expression dependent on PARP-1-activity. Forskolin stimulation of BAFs increased promoter I.3/II-occupancy by PARP-1, whereas SIRT-1 competed with PARP-1 for DNA binding but independently activated the promoter I.3/II. Consistently, the inhibition of both PARP-1 and SIRT-1 increased the NAD+/NADH-ratio in BAFs. This suggests that cellular NAD+/NADH ratios control the complex interactions of PARP-1, H1 and SIRT-1 and regulate the interplay of parylation and acetylation/de-acetylation events with low NAD+/NADH ratios (reverse Warburg effect), promoting PARP-1 activation and estrogen synthesis in BAFs. Therefore, PARP-1 inhibitors could be useful in the treatment of estrogen-dependent breast cancers.

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Coloff, Jonathan L., and Jeffrey C. Rathmell. "Metabolic regulation of Akt: roles reversed." Journal of Cell Biology 175, no. 6 (December 11, 2006): 845–47. http://dx.doi.org/10.1083/jcb.200610119.

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The respiration-deficient, highly glycolytic metabolic phenotype of cancer cells known as the “Warburg effect” has been appreciated for many years. A new study (see Pelicano et al. on p. 913 of this issue) demonstrates that respiration deficiency caused by mitochondrial mutation or hypoxia may directly promote the enormous survival advantage observed in cancer cells by activation of the phosphatidylinositol 3-kinase–Akt survival pathway. We discuss these and other recent findings that show how metabolic changes associated with cancer can play a significant role in tumor biology.

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Wang, Rui, Sheng-Yuan Wang, Yue Wang, Rui Xin, Bing Xia, Ye Xin, Tong Zhang, and Yong-Hui Wu. "The Warburg effect promoted the activation of the NLRP3 inflammasome induced by Ni-refining fumes in BEAS-2B cells." Toxicology and Industrial Health 36, no. 8 (August 2020): 580–90. http://dx.doi.org/10.1177/0748233720937197.

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Nickel (Ni) is a known human carcinogen that has an adverse effect on various human organs in occupational workers during Ni refinement and smelting. In the present study, we used real-time polymerase chain reactions, Western blot analysis, and a lactate production assay to investigate whether an increase in the NLRP3 inflammasome induced by Ni-refining fumes was associated with the Warburg effect in BEAS-2B cells, a nonmalignant pulmonary epithelial line. Exposure to Ni-refining fumes suppressed cell proliferation and increased lactate production compared with those in an untreated control group in a dose- and time-dependent manner. Ni-refining fumes induced the Warburg effect, which was observed based on increases in the levels of hypoxia-inducible factor-1α, hexokinase 2, pyruvate kinase isozyme type M2, and lactate dehydrogenase A. In addition, Ni-refining fumes promoted increased expression of NLRP3 at both the gene and protein levels. Furthermore, inhibition of the Warburg effect by 2-Deoxy-d-glucose reversed the increased expression of NLRP3 induced by Ni-refining fumes. Collectively, our data demonstrated that the Warburg effect can promote the expression of the NLRP3 inflammasome induced by the Ni-refining fumes in BEAS-2B cells. This indicates a new phenomenon in which alterations in energy production in human cells induced by Ni-refining fumes regulate the inflammatory response.

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Journal articles on the topic 'Reverse Warburg effect'

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