The SIRT1/HIF2α Axis Drives Reductive Glutamine Metabolism under Chronic Acidosis and Alters Tumor Response to Therapy
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Abstract
Extracellular tumor acidosis largely results from an exacerbated glycolytic flux in cancer and cancer-associated cells. Conversely, little is known about how tumor cells adapt their metabolism to acidosis. Here, we demonstrate that long-term exposure of cancer cells to acidic pH leads to a metabolic reprogramming toward glutamine metabolism. This switch is triggered by the need to reduce the production of protons from glycolysis and further maintained by the NAD+-dependent increase in SIRT1 deacetylase activity to ensure intracellular pH homeostasis. A consecutive increase in HIF2α activity promotes the expression of various transporters and enzymes supporting the reductive and oxidative glutamine metabolism, whereas a reduction in functional HIF1α expression consolidates the inhibition of glycolysis. Finally, in vitro and in vivo experiments document that acidosis accounts for a net increase in tumor sensitivity to inhibitors of SIRT1 and glutaminase GLS1. These findings highlight the influence that tumor acidosis and metabolism exert on each other. Cancer Res; 74(19); 5507–19. ©2014 AACR.
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Long-term exposure of cancer cells to acidic extracellular conditions induces metabolic reprogramming toward glutamine metabolism via HIF-2α activity.
“Furthermore, long-term exposure of cancer cells to acidic extracellular conditions induces metabolic reprogramming toward glutamine metabolism via HIF-2α activity71.”
From Glutamine reliance in cell metabolism (2020) · cites this paper as [71]
Cites
Understanding the Warburg Effect: The Metabolic Requirements of Cell Proliferation
Vander Heiden, M. G., Cantley, L. C., & Thompson, C. B. (2009) · Science · doi:10.1126/science.1160809 · Cited by 16,197 · see citing works
Warburg, O. (1956) · Science · doi:10.1126/science.123.3191.309 · Cited by 13,425 · see citing works
Bidirectional Transport of Amino Acids Regulates mTOR and Autophagy
Nicklin, P., Bergman, P., Zhang, B., Triantafellow, E., Wang, H., Nyfeler, B., Yang, H., Hild, M., Kung, C., Wilson, C., et al. (2009) · Cell · doi:10.1016/j.cell.2008.11.044 · Cited by 1,798 · see citing works
Reductive glutamine metabolism by IDH1 mediates lipogenesis under hypoxia
Metallo, C. M., Gameiro, P. A., Bell, E. L., Mattaini, K. R., Yang, J., Hiller, K., Jewell, C. M., Johnson, Z. R., Irvine, D. J., Guarente, L., et al. (2012) · Nature · doi:10.1038/nature10602 · Cited by 1,791 · see citing works
Glutamine addiction: a new therapeutic target in cancer
Wise, D. R., & Thompson, C. B. (2010) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2010.05.003 · Cited by 1,770 · see citing works
Acidity Generated by the Tumor Microenvironment Drives Local Invasion
Estrella, V. C., Chen, T., Lloyd, M. C., Wojtkowiak, J. W., Cornnell, H. H., Ibrahim‐Hashim, A., Bailey, K. M., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-2796 · Cited by 1,404 · see citing works
Q's next: the diverse functions of glutamine in metabolism, cell biology and cancer
DeBerardinis, R. J., & Cheng, T. (2010) · Oncogene · doi:10.1038/onc.2009.358 · Cited by 1,365 · see citing works
Glutamine and cancer: cell biology, physiology, and clinical opportunities
Hensley, C. T., Wasti, A. T., & DeBerardinis, R. J. (2013) · Journal of Clinical Investigation · doi:10.1172/jci69600 · Cited by 1,262 · see citing works
The role of disturbed pH dynamics and the Na+/H+ exchanger in metastasis
Cardone, R. A., Casavola, V., & Reshkin, S. J. (2005) · Nature Reviews Cancer · doi:10.1038/nrc1713 · Cited by 897 · see citing works
Végran, F., Boidot, R., Michiels, C., Sonveaux, P., & Feron, O. (2011) · Cancer Research · doi:10.1158/0008-5472.can-10-2828 · Cited by 816 · see citing works
Sirtuin 1 Modulates Cellular Responses to Hypoxia by Deacetylating Hypoxia-Inducible Factor 1α
Lim, J.-H., Lee, Y.-M., Chun, Y.-S., Chen, J., Kim, J.-E., & Park, J.-W. (2010) · Molecular Cell · doi:10.1016/j.molcel.2010.05.023 · Cited by 758 · see citing works
A microenvironmental model of carcinogenesis
Gatenby, R. A., & Gillies, R. J. (2007) · Nature reviews. Cancer · doi:10.1038/nrc2255 · Cited by 725 · see citing works
Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime?
Fuchs, B. C., & Bode, B. (2005) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2005.04.005 · Cited by 717 · see citing works
Rofstad, E. K., Mathiesen, B. S., Kindem, K., & Galappathi, K. (2006) · Cancer Research · doi:10.1158/0008-5472.can-06-0983 · Cited by 668 · see citing works
Solomon, J. M., Pasupuleti, R., Xu, L., McDonagh, T., Curtis, R., DiStefano, P. S., & Huber, L. J. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.26.1.28-38.2006 · Cited by 481 · see citing works
American Association for Cancer Research
Salgaller, M. L. (2000) · Expert Opinion on Investigational Drugs · doi:10.1517/13543784.9.6.1413 · Cited by 474 · see citing works
Regulation of Hypoxia-Inducible Factor 2α Signaling by the Stress-Responsive Deacetylase Sirtuin 1
Dioum, E. M., Chen, R., Alexander, M. S., Zhang, Q., Hogg, R. T., Gerard, R. D., & Garcia, J. A. (2009) · Science · doi:10.1126/science.1169956 · Cited by 470 · see citing works
Fukumura, D., Xu, L., Chen, Y., Gohongi, T., Seed, B., & Jain, R. K. (2001) · PubMed · Cited by 438 · see citing works
Sirtuins — novel therapeutic targets to treat age-associated diseases
Lavu, S., Boss, O., Elliott, P. J., & Lambert, P. (2008) · Nature Reviews Drug Discovery · doi:10.1038/nrd2665 · Cited by 425 · see citing works
Doherty, J. R., Yang, C., Scott, K. E. N., Cameron, M. D., Fallahi, M., Li, W., Hall, M. A., Amelio, A. L., Mishra, J. K., Li, F., et al. (2013) · Cancer Research · doi:10.1158/0008-5472.can-13-2034 · Cited by 399 · see citing works
Robinson, M. M., McBryant, S. J., Tsukamoto, T., Rojas, C. J., Ferraris, D. V., Hamilton, S. K., Hansen, J. C., & Curthoys, N. P. (2007) · Biochemical Journal · doi:10.1042/bj20070039 · Cited by 344 · see citing works
Xu, L., Fukumura, D., & Jain, R. K. (2002) · Journal of Biological Chemistry · doi:10.1074/jbc.m108347200 · Cited by 281 · see citing works
Histone Acetylation Regulates Intracellular pH
McBrian, M. A., Behbahan, I. S., Ferrari, R., Su, T., Huang, T.-W., Li, K., Hong, C. S., Christofk, H. R., Vogelauer, M., Seligson, D. B., et al. (2013) · Molecular Cell · doi:10.1016/j.molcel.2012.10.025 · Cited by 272 · see citing works
Contributions of Cell Metabolism and H+ Diffusion to the Acidic pH of Tumors
Schornack, P. A., & Gillies, R. J. (2003) · Neoplasia · doi:10.1016/s1476-5586(03)80005-2 · Cited by 263 · see citing works
Lorenz, M. A., Burant, C., & Kennedy, R. T. (2011) · Analytical Chemistry · doi:10.1021/ac103313x · Cited by 233 · see citing works
Polet, F., & Féron, O. (2013) · Journal of Internal Medicine · doi:10.1111/joim.12016 · Cited by 232 · see citing works
Self-citationHypoxia and energetic tumour metabolism
Brahimi-Horn, M. C., Bellot, G. L., & Pouysségur, J. (2010) · Current Opinion in Genetics & Development · doi:10.1016/j.gde.2010.10.006 · Cited by 228 · see citing works
Acidosis induces reprogramming of cellular metabolism to mitigate oxidative stress
LaMonte, G., Tang, X., Chen, J. L.-Y., Wu, J., Ding, C. C., Keenan, M. M., Sangokoya, C., Kung, H., Ilkayeva, O., Boros, L. G., et al. (2013) · Cancer & Metabolism · doi:10.1186/2049-3002-1-23 · Cited by 219 · see citing works
The Genomic Analysis of Lactic Acidosis and Acidosis Response in Human Cancers
Chen, J. L.-Y., Lucas, J. E., Schroeder, T., Mori, S., Wu, J., Nevins, J. R., Dewhirst, M. W., West, M., & Chi, J. (2008) · PLoS Genetics · doi:10.1371/journal.pgen.1000293 · Cited by 214 · see citing works
Clastogenicity of low pH to various cultured mammalian cells
Morita, T., Nagaki, T., Fukuda, I., & OKUMURA, K. (1992) · Mutation research. Fundamental and molecular mechanisms of mutagenesis · doi:10.1016/0027-5107(92)90235-t · Cited by 209 · see citing works
Acid treatment of melanoma cells selects for invasive phenotypes
Moellering, R. E., Black, K. C. L., Krishnamurty, C., Baggett, B. K., Stafford, P., Rain, M., Gatenby, R. A., & Gillies, R. J. (2008) · Clinical & Experimental Metastasis · doi:10.1007/s10585-008-9145-7 · Cited by 206 · see citing works
Kaelin, W. G., & Thompson, C. B. (2010) · Nature · doi:10.1038/465562a · Cited by 198 · see citing works
Messonnier, L., Kristensen, M., Juel, C., & Denis, C. (2007) · Journal of applied physiology · doi:10.1152/japplphysiol.00691.2006 · Cited by 164 · see citing works
Nγ-Aryl glutamine analogues as probes of the ASCT2 neutral amino acid transporter binding site
Esslinger, C. S., Cybulski, K. A., & Rhoderick, J. F. (2004) · Bioorganic & Medicinal Chemistry · doi:10.1016/j.bmc.2004.11.028 · Cited by 151 · see citing works
Regulation of intracellular pH in human melanoma: potential therapeutic implications.
Wahl, M., Owen, J. A., Burd, R., Herlands, R., Nogami, S. S., Rodeck, U., Berd, D., Leeper, D. B., & Owen, C. S. (2002) · PubMed · Cited by 141 · see citing works
pH distributions in spontaneous and isotransplanted rat tumours
Kallinowski, F., & Vaupel, P. W. (1988) · British Journal of Cancer · doi:10.1038/bjc.1988.210 · Cited by 85 · see citing works
Acidic pH via NF-κB favours VEGF-C expression in human melanoma cells
Peppicelli, S., Bianchini, F., Contena, C., Tombaccini, D., & Calorini, L. (2013) · Clinical & Experimental Metastasis · doi:10.1007/s10585-013-9595-4 · Cited by 55 · see citing works
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The Acidic Tumor Microenvironment as a Driver of Cancer
Boedtkjer, E., & Pedersen, S. F. (2019) · Annual Review of Physiology · doi:10.1146/annurev-physiol-021119-034627 · Cited by 1,248 · see citing works
NAD(H) and NADP(H) Redox Couples and Cellular Energy Metabolism
Xiao, W., Wang, R., Handy, D. E., & Loscalzo, J. (2017) · Antioxidants and Redox Signaling · doi:10.1089/ars.2017.7216 · Cited by 1,062 · see citing works
Glutamine reliance in cell metabolism
Yoo, H. C., Yu, Y. C., Sung, Y., & Han, J. M. (2020) · Experimental & Molecular Medicine · doi:10.1038/s12276-020-00504-8 · Cited by 1,021 · see citing works
Tumour acidosis: from the passenger to the driver's seat
Corbet, C., & Féron, O. (2017) · Nature reviews. Cancer · doi:10.1038/nrc.2017.77 · Cited by 1,000 · see citing works
Self-citationMonocarboxylate transporters in cancer
Payen, V. L., Mina, E., Hée, V. F. V., Porporato, P. E., & Sonveaux, P. (2019) · Molecular Metabolism · doi:10.1016/j.molmet.2019.07.006 · Cited by 665 · see citing works
A roadmap for interpreting 13C metabolite labeling patterns from cells
Buescher, J. M., Antoniewicz, M. R., Boros, L. G., Burgess, S. C., Brunengraber, H., Clish, C. B., DeBerardinis, R. J., Féron, O., Frezza, C., Ghesquière, B., et al. (2015) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2015.02.003 · Cited by 623 · see citing works
The effect of HIF on metabolism and immunity
Taylor, C. T., & Scholz, C. C. (2022) · Nature Reviews Nephrology · doi:10.1038/s41581-022-00587-8 · Cited by 517 · see citing works
Dierge, E., Debock, E., Guilbaud, C., Corbet, C., Mignolet, É., Mignard, L., Bastien, E., Dessy, C., Larondelle, Y., & Féron, O. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.05.016 · Cited by 505 · see citing works
Self-citationMonocarboxylate transporters in the brain and in cancer
Pérez‐Escuredo, J., Hée, V. F. V., Sboarina, M., Falces, J., Payen, V. L., Pellerin, L., & Sonveaux, P. (2016) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2016.03.013 · Cited by 407 · see citing works
Corbet, C., Pinto, A., Martherus, R., de Jesus, J. T. C. L., Polet, F., & Féron, O. (2016) · Cell Metabolism · doi:10.1016/j.cmet.2016.07.003 · Cited by 335 · see citing works
Self-citationEndothelial Cell Metabolism in Health and Disease
Rohlenová, K., Veys, K., Santos, I. M., Bock, K. D., & Carmeliet, P. (2017) · Trends in Cell Biology · doi:10.1016/j.tcb.2017.10.010 · Cited by 336 · see citing works
Corbet, C., Bastien, E., de Jesus, J. T. C. L., Dierge, E., Martherus, R., Linden, C. V., Doix, B., Degavre, C., Guilbaud, C., Petit, L., et al. (2020) · Nature Communications · doi:10.1038/s41467-019-14262-3 · Cited by 327 · see citing works
Self-citationCauses, consequences, and therapy of tumors acidosis
Pillai, S., Damaghi, M., Marunaka, Y., Spugnini, E. P., Fais, S., & Gillies, R. J. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09792-7 · Cited by 282 · see citing works
Amino acid metabolism in tumor biology and therapy
Chen, J., Cui, L., Lu, S., & Xu, S. (2024) · Cell Death and Disease · doi:10.1038/s41419-024-06435-w · Cited by 268 · see citing works
Hypoxia-induced signaling in the cardiovascular system: pathogenesis and therapeutic targets
Zhao, Y., Xiong, W., Li, C., Zhao, R., Lu, H., Song, S., Zhou, Y., Hu, Y., Shi, B., & Ge, J. (2023) · Signal Transduction and Targeted Therapy · doi:10.1038/s41392-023-01652-9 · Cited by 264 · see citing works
Hypoxia as a driver of resistance to immunotherapy
Kopecka, J., Salaroglio, I. C., Pérez-Ruiz, E., Sarmento‐Ribeiro, A. B., Saponara, S., Rivas, J. D. L., & Riganti, C. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100787 · Cited by 252 · see citing works
Rohani, N., Hao, L., Alexis, M. S., Joughin, B. A., Krismer, K., Moufarrej, M. N., Soltis, A. R., Lauffenburger, D. A., Yaffe, M. B., Burge, C. B., et al. (2019) · Cancer Research · doi:10.1158/0008-5472.can-18-1604 · Cited by 243 · see citing works
Lactate promotes glutamine uptake and metabolism in oxidative cancer cells
Pérez-Escuredo, J., Dadhich, R. K., Dhup, S., Cacace, A., Van Hée, V. F., De Saedeleer, C. J., Sboarina, M., Rodriguez, F., Fontenille, M.-J., Brisson, L., et al. (2016) · Cell Cycle · doi:10.1080/15384101.2015.1120930 · Cited by 231 · see citing works
Ganapathy-Kanniappan, S. (2018) · Critical Reviews in Biochemistry and Molecular Biology · doi:10.1080/10409238.2018.1556578 · Cited by 216 · see citing works
The emerging role of lactate in tumor microenvironment and its clinical relevance
Chen, S., Xu, Y., Zhuo, W., & Zhang, L. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.216837 · Cited by 200 · see citing works
Corbet, C., Bastien, E., Draoui, N., Doix, B., Mignion, L., Jordan, B. F., Marchand, A., Vanherck, J., Chaltin, P., Schakman, O., et al. (2018) · Nature Communications · doi:10.1038/s41467-018-03525-0 · Cited by 189 · see citing works
Self-citationThe impact of tumour pH on cancer progression: strategies for clinical intervention
Ward, C., Meehan, J., Gray, M., Murray, A. F., Argyle, D. J., Kunkler, I. H., & Langdon, S. P. (2020) · Exploration of Targeted Anti-tumor Therapy · doi:10.37349/etat.2020.00005 · Cited by 180 · see citing works
Metabolic heterogeneity in cancer
Demicco, M., Liu, X., Leithner, K., & Fendt, S. (2024) · Nature Metabolism · doi:10.1038/s42255-023-00963-z · Cited by 183 · see citing works
Cancer cell metabolism and mitochondria: Nutrient plasticity for TCA cycle fueling
Corbet, C., & Féron, O. (2017) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2017.01.002 · Cited by 170 · see citing works
Self-citationImpact of cancer metabolism on therapy resistance – Clinical implications
Gonçalves, A. C., Richiardone, E., Jorge, J., Polónia, B. R. G., Xavier, C. P. R., Salaroglio, I. C., Riganti, C., Vasconcelos, M. H., Corbet, C., & Sarmento‐Ribeiro, A. B. (2021) · Drug Resistance Updates · doi:10.1016/j.drup.2021.100797 · Cited by 170 · see citing works
Self-citationTherapeutic targeting of glutaminolysis as an essential strategy to combat cancer
Matés, J. M., Paola, F. J. D., Campos-Sandoval, J. A., Mazurek, S., & Márquez, J. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.012 · Cited by 164 · see citing works
pH sensing at the intersection of tissue homeostasis and inflammation
Hajjar, S., & Zhou, X. (2023) · Trends in Immunology · doi:10.1016/j.it.2023.08.008 · Cited by 158 · see citing works
Hypoxia Dictates Metabolic Rewiring of Tumors: Implications for Chemoresistance
Belisario, D. C., Kopecka, J., Pasino, M., Akman, M., De Smaele, E., Donadelli, M., & Riganti, C. (2020) · Cells · doi:10.3390/cells9122598 · Cited by 133 · see citing works
Glutamine Addiction and Therapeutic Strategies in Lung Cancer
Vanhove, K., Derveaux, E., Graulus, G., Mesotten, L., Thomeer, M., Noben, J., Guedens, W., & Adriaensens, P. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20020252 · Cited by 128 · see citing works
Zhang, Q., Lou, Y., Zhang, J., Fu, Q., Wei, T., Sun, X., Chen, Q., Yang, J., Bai, X., & Liang, T. (2017) · Molecular Cancer · doi:10.1186/s12943-017-0689-5 · Cited by 127 · see citing works
Adiponectin triggers breast cancer cell death via fatty acid metabolic reprogramming
Pham, D., & Park, P. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02223-y · Cited by 118 · see citing works
The roles of sirtuins family in cell metabolism during tumor development
Zhu, S., Dong, Z., Ke, X., Hou, J., Zhao, E., Zhang, K., Wang, F., Yang, L., Xiang, Z., & Cui, H. (2018) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2018.11.003 · Cited by 113 · see citing works
How protons pave the way to aggressive cancers
Swietach, P., Boedtkjer, E., & Pedersen, S. F. (2023) · Nature reviews. Cancer · doi:10.1038/s41568-023-00628-9 · Cited by 112 · see citing works
Cancer heterogeneity is not compatible with one unique cancer cell metabolic map
Strickaert, A., Saiselet, M., Dom, G., Deken, X. D., Dumont, J. E., Féron, O., Sonveaux, P., & Maenhaut, C. (2016) · Oncogene · doi:10.1038/onc.2016.411 · Cited by 106 · see citing works
Tian, Y., Yang, B., Qiu, W., Hao, Y., Zhang, Z., Yang, B., Li, N., Cheng, S., Lin, Z., Rui, Y., et al. (2019) · Nature Communications · doi:10.1038/s41467-019-11274-x · Cited by 105 · see citing works
den Bossche, V. V., Zaryouh, H., Vara-Messler, M., Vignau, J., Machiels, J., Wouters, A., Schmitz, S., & Corbet, C. (2022) · Drug Resistance Updates · doi:10.1016/j.drup.2022.100806 · Cited by 102 · see citing works
Self-citationTherapeutic implications of tumor interstitial acidification
Kolosenko, I., Avnet, S., Baldini, N., Viklund, J., & Milito, A. D. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.01.008 · Cited by 100 · see citing works
Glutamine addiction in tumor cell: oncogene regulation and clinical treatment
Li, X., Peng, X., Li, Y., Wei, S., He, G., Liu, J., Li, X., Yang, S., Dai, L., Lin, W., et al. (2024) · Cell Communication and Signaling · doi:10.1186/s12964-023-01449-x · Cited by 99 · see citing works
Xiao, Z.-P., Lv, T., Hou, P.-P., Manaenko, A., Liu, Y., Jin, Y., Gao, L., Jia, F., Tian, Y., Li, P., et al. (2021) · Stroke · doi:10.1161/strokeaha.121.034850 · Cited by 93 · see citing works
Corbet, C., Ragelle, H., Pourcelle, V., Vanvarenberg, K., Marchand‐Brynaert, J., Véronique Préat, A., & Féron, O. (2015) · Journal of Controlled Release · doi:10.1016/j.jconrel.2015.12.020 · Cited by 87 · see citing works
Self-citationDlx-2 and glutaminase upregulate epithelial-mesenchymal transition and glycolytic switch
Lee, S. Y., Jeon, H. M., Ju, M. K., Jeong, E. K., Kim, C. H., Park, H. G., Han, S. I., & Kang, H. S. (2016) · Oncotarget · doi:10.18632/oncotarget.6879 · Cited by 82 · see citing works
Sirtuins and the Metabolic Hurdles in Cancer
German, N. J., & Haigis, M. C. (2015) · Current Biology · doi:10.1016/j.cub.2015.05.012 · Cited by 84 · see citing works
Tumour acidosis evaluated in vivo by MRI-CEST pH imaging reveals breast cancer metastatic potential
Anemone, A., Consolino, L., Conti, L., Irrera, P., Hsu, M. Y., Villano, D., Dastrù, W., Porporato, P. E., Cavallo, F., & Longo, D. L. (2020) · British Journal of Cancer · doi:10.1038/s41416-020-01173-0 · Cited by 80 · see citing works
Glutamine activates STAT3 to control cancer cell proliferation independently of glutamine metabolism
Cacace, A., Sboarina, M., Vazeille, T., & Sonveaux, P. (2017) · Oncogene · doi:10.1038/onc.2016.364 · Cited by 76 · see citing works
Hu, P., Li, S., Tian, N., Wu, F., Hu, Y., Li, D., Qi, Y., Wei, Z., Wei, Q., Li, Y., et al. (2019) · Cell Death and Disease · doi:10.1038/s41419-018-1242-1 · Cited by 76 · see citing works
The pyruvate dehydrogenase complex: Life’s essential, vulnerable and druggable energy homeostat
Stacpoole, P. W., & McCall, C. E. (2023) · Mitochondrion · doi:10.1016/j.mito.2023.02.007 · Cited by 68 · see citing works
Polet, F., Corbet, C., Pinto, A., Rubio, L. I., Martherus, R., Bol, V., Drozak, X., Grégoire, V., Riant, O., & Féron, O. (2015) · Oncotarget · doi:10.18632/oncotarget.6426 · Cited by 66 · see citing works
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Zhu, C., Yang, J., Zheng, J., Chen, S., Huang, F., & Yang, R. (2019) · Analytical Chemistry · doi:10.1021/acs.analchem.9b03659 · Cited by 62 · see citing works
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Comito, G., Ippolito, L., Chiarugi, P., & Cirri, P. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.00396 · Cited by 61 · see citing works
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Corbet, C., & Féron, O. (2015) · Current Opinion in Clinical Nutrition & Metabolic Care · doi:10.1097/mco.0000000000000178 · Cited by 60 · see citing works
Self-citationMichl, J., Wang, Y., Monterisi, S., Błaszczak, W., Beveridge, R. D. D., Bridges, E., Koth, J., Bodmer, W. F., & Swietach, P. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110493 · Cited by 59 · see citing works
Chronic acidosis rewires cancer cell metabolism through PPARα signaling
Rolver, M. G., Holland, L. K. K., Ponniah, M., Prasad, N. S., Yao, J., Schnipper, J., Kramer, S. H., Elingaard-Larsen, L. O., Pedraz‐Cuesta, E., Liu, B., et al. (2022) · International Journal of Cancer · doi:10.1002/ijc.34404 · Cited by 58 · see citing works
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Baldini, N., & Avnet, S. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms20010126 · Cited by 57 · see citing works
Benyahia, Z., Blackman, M. C. N. M., Hamelin, L., Zampieri, L. X., Capelôa, T., Bedin, M., Vazeille, T., Schakman, O., & Sonveaux, P. (2021) · Cancers · doi:10.3390/cancers13030569 · Cited by 58 · see citing works
Targeting Mitochondrial Function to Treat Quiescent Tumor Cells in Solid Tumors
Zhang, X., Milito, A. D., Olofsson, A. M., Gullbo, J., D’Arcy, P., & Linder, S. T. (2015) · International Journal of Molecular Sciences · doi:10.3390/ijms161126020 · Cited by 56 · see citing works
Therapeutic Targeting of Cancer Stem Cells: Integrating and Exploiting the Acidic Niche
Linden, C. V., & Corbet, C. (2019) · Frontiers in Oncology · doi:10.3389/fonc.2019.00159 · Cited by 58 · see citing works
Self-citationMagnesium metal and its corrosion products: Promising materials for tumor interventional therapy
Xu, B., Song, Y., Yang, K., Li, Y., Chen, B., Liao, X., & Jia, Q. (2023) · Journal of Magnesium and Alloys · doi:10.1016/j.jma.2023.02.007 · Cited by 55 · see citing works
Pillai, S., Mahmud, I., Mahar, R., Griffith, C., Langsen, M., Nguyen, J. V., Wojtkowiak, J. W., Swietach, P., Gatenby, R. A., Bui, M. M., et al. (2022) · Cell Reports · doi:10.1016/j.celrep.2022.110796 · Cited by 52 · see citing works
O-GlcNAcylation: key regulator of glycolytic pathways
Bacigalupa, Z. A., Bhadiadra, C., & Reginato, M. J. (2018) · Journal of Bioenergetics and Biomembranes · doi:10.1007/s10863-018-9742-3 · Cited by 52 · see citing works
Yu, H., Li, J., Peng, S., Liu, Q., Chen, D., He, Z., Xiang, J., & Wang, B. (2024) · Cancer Letters · doi:10.1016/j.canlet.2024.217385 · Cited by 55 · see citing works
The Interplay of Dysregulated pH and Electrolyte Imbalance in Cancer
Alfarouk, K. O., Ahmed, S. B. M., Ahmed, A., Elliott, R. L., Ibrahim, M. E., Ali, H. S., Wales, C. C., Nourwali, I., Aljarbou, A. N., Bashir, A. H. H., et al. (2020) · Cancers · doi:10.3390/cancers12040898 · Cited by 52 · see citing works
FDG uptake in cancer: a continuing debate
Peppicelli, S., Andreucci, E., Ruzzolini, J., Bianchini, F., & Calorini, L. (2020) · Theranostics · doi:10.7150/thno.40599 · Cited by 50 · see citing works
Treps, L., Conradi, L., Harjes, U., & Carmeliet, P. (2016) · Pharmacological Reviews · doi:10.1124/pr.116.012492 · Cited by 49 · see citing works
Regulation of inflammatory responses by pH-dependent transcriptional condensates
Wu, Z., Pope, S. D., Ahmed, N. S., Leung, D. L., Hong, Y., Hajjar, S., Krabak, C., Zhong, Z., Raghunathan, K., Yue, Q., et al. (2025) · Cell · doi:10.1016/j.cell.2025.06.033 · Cited by 46 · see citing works
Physicochemical aspects of the tumour microenvironment as drivers of vasculogenic mimicry
Andreucci, E., Peppicelli, S., Ruzzolini, J., Bianchini, F., & Calorini, L. (2022) · Cancer and Metastasis Reviews · doi:10.1007/s10555-022-10067-x · Cited by 43 · see citing works
Role of Sirtuins in Tumor Angiogenesis
Edatt, L., Poyyakkara, A., Raji, G. R., Ramachandran, V., Shankar, S. S., & Kumar, V. B. S. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2019.01516 · Cited by 43 · see citing works
The Fate of Glutamine in Human Metabolism. The Interplay with Glucose in Proliferating Cells
Mazat, J., & Ransac, S. (2019) · Metabolites · doi:10.3390/metabo9050081 · Cited by 43 · see citing works
Trempolec, N., Degavre, C., Doix, B., Brusa, D., Corbet, C., & Féron, O. (2020) · Cancers · doi:10.3390/cancers12051284 · Cited by 42 · see citing works
Self-citationFéron, O. (2019) · Annals of Translational Medicine · doi:10.21037/atm.2019.11.140 · Cited by 38 · see citing works
Andersen, H. B., Ialchina, R., Pedersen, S. F., & Czaplińska, D. (2021) · Cancer and Metastasis Reviews · doi:10.1007/s10555-021-10004-4 · Cited by 40 · see citing works
Bouthelier, A., & Aragonés, J. (2020) · Biochimica et Biophysica Acta (BBA) - Molecular Cell Research · doi:10.1016/j.bbamcr.2020.118733 · Cited by 36 · see citing works
Daverio, Z., Balcerczyk, A., Rautureau, G. J. P., & Panthu, B. (2023) · Cancers · doi:10.3390/cancers15051417 · Cited by 35 · see citing works
Pinto, A., Macé, Y., Drouet, F., Bony, E., Boidot, R., Draoui, N., Lobysheva, I. I., Corbet, C., Polet, F., Martherus, R., et al. (2015) · Oncogene · doi:10.1038/onc.2015.474 · Cited by 33 · see citing works
Self-citationChano, T., Avnet, S., Kusuzaki, K., Bonuccelli, G., Sonveaux, P., Rotili, D., Mai, A., & Baldini, N. (2016) · PubMed Central · Cited by 34 · see citing works
Linden, C. V., & Corbet, C. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.016 · Cited by 34 · see citing works
Self-citationCzaplińska, D., Ialchina, R., Andersen, H. B., Yao, J., Stigliani, A., Dannesboe, J., Flinck, M., Chen, X., Mitrega, J., Gnosa, S. P., et al. (2022) · International Journal of Cancer · doi:10.1002/ijc.34367 · Cited by 34 · see citing works
Role of Sirtuins in Maintenance of Genomic Stability: Relevance to Cancer and Healthy Aging
Wu, X., Neng, C., Fenech, M. F., & Wang, X. (2016) · DNA and Cell Biology · doi:10.1089/dna.2016.3280 · Cited by 33 · see citing works
Zhou, Z., Wang, Q., Mao, L., Li, X., Liu, P., Song, J., Liu, X., Xu, F., Lei, J., & He, S. (2019) · Cell Cycle · doi:10.1080/15384101.2019.1578145 · Cited by 33 · see citing works
Dumas, J., Brisson, L., Chevalier, S., Mahéo, K., Fromont, G., Moussata, D., Besson, P., & Roger, S. (2017) · Seminars in Cancer Biology · doi:10.1016/j.semcancer.2017.03.004 · Cited by 33 · see citing works
Yao, J., Czaplińska, D., Ialchina, R., Schnipper, J., Liu, B., Sandelin, A., & Pedersen, S. F. (2020) · Cancers · doi:10.3390/cancers12082183 · Cited by 32 · see citing works
A “Weird” Mitochondrial Fatty Acid Oxidation as a Metabolic “Secret” of Cancer
Zhelev, Z., Aoki, I., Lazarova, D., Vlaykova, T. I., Higashi, T., & Bakalova, R. (2022) · Oxidative Medicine and Cellular Longevity · doi:10.1155/2022/2339584 · Cited by 33 · see citing works
From old to new — Repurposing drugs to target mitochondrial energy metabolism in cancer
Aminzadeh-Gohari, S., Weber, D. D., Vidali, S., Catalano, L., Kofler, B., & Feichtinger, R. G. (2019) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2019.05.025 · Cited by 33 · see citing works
Cortini, M., Armirotti, A., Columbaro, M., Longo, D. L., Pompo, G. D., Cannas, E., Maresca, A., Errani, C., Longhi, A., Righi, A., et al. (2021) · Cancers · doi:10.3390/cancers13020311 · Cited by 31 · see citing works
Hée, V. F. V., Labar, D., Dehon, G., Grasso, D., Grégoire, V., Muccioli, G. G., Frédérick, R., & Sonveaux, P. (2017) · Oncotarget · doi:10.18632/oncotarget.14705 · Cited by 31 · see citing works
Yin, Z., Shen, G., Fan, M., & Zheng, P. (2025) · Journal of bone oncology · doi:10.1016/j.jbo.2025.100660 · Cited by 29 · see citing works
Schoonjans, C. A., Joudiou, N., Brusa, D., Corbet, C., Féron, O., & Gallez, B. (2019) · Cancer Letters · doi:10.1016/j.canlet.2019.12.003 · Cited by 28 · see citing works
Self-citationVenkateswaran, G., & Dedhar, S. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.602668 · Cited by 28 · see citing works
Chen, S., Ning, B., Song, J., Yang, Z., Zhou, L., Chen, Z., Mao, L., Liu, H., Wang, Q., He, S., et al. (2022) · International Journal of Biological Sciences · doi:10.7150/ijbs.69526 · Cited by 28 · see citing works
Metabolic and Amino Acid Alterations of the Tumor Microenvironment
Štěpka, P., Všianský, V., Raudenská, M., Gumulec, J., Adam, V., & Masařík, M. (2020) · Current Medicinal Chemistry · doi:10.2174/0929867327666200207114658 · Cited by 28 · see citing works
MBD3 mediates epigenetic regulation on EPAS1 promoter in cancer
Cui, J., Duan, B., Zhao, X., Chen, Y., Sun, S., Deng, W., Zhang, Y., Du, J., Chen, Y., & Gu, L. (2016) · Tumor Biology · doi:10.1007/s13277-016-5237-1 · Cited by 26 · see citing works
Voss, N. C. S., Dreyer, T., Henningsen, M. B., Vahl, P., Honoré, B., & Boedtkjer, E. (2020) · Cancers · doi:10.3390/cancers12040891 · Cited by 27 · see citing works
Activation of amino acid metabolic program in cardiac HIF1-alpha-deficient mice
Menendez-Montes, I., Escobar, B., Gómez, M. J., Albendea-Gomez, T., Palacios, B., Bonzón‐Kulichenko, E., Izquierdo-García, J. L., Alonso, A. V., Ferrarini, A., Jiménez‐Borreguero, L. J., et al. (2021) · iScience · doi:10.1016/j.isci.2021.102124 · Cited by 26 · see citing works
Bång-Rudenstam, A., Cerezo-Magaña, M., & Belting, M. (2019) · Cancer and Metastasis Reviews · doi:10.1007/s10555-019-09786-5 · Cited by 25 · see citing works
The solid tumor microenvironment and related targeting strategies: a concise review
Wang, Y., Zhou, H., Ju, S., Dong, X., & Zheng, C. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1563858 · Cited by 28 · see citing works
Oxidative and Glycolytic Metabolism: Their Reciprocal Regulation and Dysregulation in Cancer
Cordani, M., Rumio, C., Bontempi, G., Strippoli, R., & Marcucci, F. (2025) · Cells · doi:10.3390/cells14151177 · Cited by 26 · see citing works
Yan, R., Cai, H., Zhou, X., Bao, G., Bai, Z., & Ge, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1344971 · Cited by 24 · see citing works
Shu, X., Li, J., Chan, U. I., Su, S. M., Shi, C., Zhang, X., An, T., Xu, J., Mo, L., Liu, J., et al. (2023) · Cancer Research · doi:10.1158/0008-5472.can-22-3398 · Cited by 24 · see citing works
Moiz, B., Garcia, J., Basehore, S. E., Sun, A., Li, A., Padmanabhan, S., Albus, K., Jang, C., Sriram, G., & Clyne, A. M. (2021) · Metabolites · doi:10.3390/metabo11040226 · Cited by 22 · see citing works
- Authors
- Corbet, C., Draoui, N., Polet, F., Pinto, A., Drozak, X., Riant, O., & Feron, O.
- Affiliations
- UCLouvain (BE)
- 1Pole of Pharmacology and Therapeutics (FATH), Institut de Recherche Expérimentale et Clinique (IREC), Université catholique de Louvain, Brussels, Belgium.
- Venue
- Cancer Research
- Published
- 2014-09-30
- Volume
- 74
- Issue
- 19
- Pages
- 5507-5519
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2099667863
- Cited by
- 169
- References
- 37
- Citations by year
- 2026: 8 · 2025: 17 · 2024: 19 · 2023: 12 · 2022: 20 · 2021: 16 · 2020: 23 · 2019: 20 · 2018: 7 · 2017: 8 · 2016: 9 · 2015: 10
- FWCI
- 2.89
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Libraries (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Hypoxia, and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Amino Acid Enzymes and Metabolism
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cancer Research › Cancer, Lipids, and Metabolism
- Keywords
- tumor acidosis, SIRT1, HIF-2α, HIF-1α, glutamine metabolism, glycolysis, intracellular pH homeostasis, NAD+-dependent deacetylation, SIRT1 inhibitors, tumor metabolic reprogramming, cancer therapy response
- MeSH terms
- Endothelial PAS Domain-Containing Protein 1, Acidosis, Chronic Disease, Glucose, Glutamine, Glycolysis, Humans, Neoplasms, Cell Line, Tumor, Basic Helix-Loop-Helix Transcription Factors, Basic Helix-Loop-Helix Proteins, Sirtuin 1
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