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The Mechanisms of Regulation of Aerobic Glycolysis (Warburg Effect) by Oncoproteins in Carcinogenesis

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Abstract

According to modern concepts, tumor formation is associated with impairments in the structure of protooncogenes and/or deactivation of suppressor genes, regardless of the nature of carcinogenic factor. As a consequence, unregulated onco-proteins activate extracellular proteases, resulting in the destruction of the extracellular matrix, which facilitates cell invasion, deterioration of the cell-cell contacts, and metastasis. Tumor development requires activation of certain transcription factors; however, many oncoproteins are not transcription factors. It can be assumed that these oncoproteins are not the ultimate effectors of tumor development, but rather transmitters of the carcinogenic signal to the transcription factors promoting tumorigenesis. Here, we describe the mechanisms of carcinogenesis caused by various oncogenes/oncoproteins. We conclude that the common feature of these mechanisms is stimulation of aerobic glycolysis (Warburg effect) regulated, as a rule, through the activation of the HIFα transcription factor. The role of aerobic glycolysis at the early stages of carcinogenesis is discussed.

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Abbreviations

ARNT:

aryl hydrocarbon receptor nuclear translocator

MCT:

monocarboxylate transporter

NOX:

NADPH oxidase complex

ROS:

reactive oxygen species

References

  1. Estrella, V., Chen, T., Lloyd, M., Wojtkowiak, J., Cornnell, H. H., Ibrahim-Hashim, A., Bailey, K., Balagurunathan, Y., Rothberg, J. M., Sloane, B. F., Johnson, J., Gatenby, R. A., and Gillies, R. J. (2013) Acidity generated by the tumor microenvironment drives local invasion, Cancer Res., 73, 1524–1535, doi: https://doi.org/10.1158/0008-5472.CAN-12-2796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. McCarty, M. F., and Whitaker, J. (2010) Manipulating tumor acidification as a cancer treatment strategy, Altern. Med. Rev., 15, 264–272.

    PubMed  Google Scholar 

  3. Martin, N. K., Robey, I. F., Gaffney, E. A., Gillies, R. J., Gatenby, R. A., and Maini, P. K. (2012) Predicting the safety and efficacy of buffer therapy to raise tumor pHe: an integrative modelling study, Br. J. Cancer, 106, 1280–1287, doi: https://doi.org/10.1038/bjc.2012.58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Harguindey, S., Arranz, J. L., Polo Orozco, J. D., Rauch, C., Fais, S., Cardone, R. A., and Reshkin, S. J. (2013). Cariporide and other new and powerful NHE1 inhibitors as potentially selective anticancer drugs - an integral molecular/biochemical/metabolic/clinical approach after one hundred years of cancer research, J. Transl. Med., 11, 282, doi: https://doi.org/10.1186/1479-5876-11-282.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  5. Schlaepfer, I. R., Glode, L. M., Hitz, C. A., Pac, C. T., Boyle, K. E., Maroni, P., Deep, G., Agarwal, R., Lucia, S. M., Cramer, S. D., Serkova, N. J., and Eckel, R. H. (2015) Inhibition of lipid oxidation increases glucose metabolism and enhances 2-deoxy-2-[(18)F]fluoro-D-glucose uptake in prostate cancer mouse xenografts, Mol. Imaging Biol., 17, 529–538, doi: https://doi.org/10.1007/s11307-014-0814-4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Guan, Z. W., Xu, B. X., Wang, R. M., Sun, L., and Tian, J. H. (2013) Hyperaccumulation of (18)F-FDG in order to differentiate solid pseudopapillary tumors from adenocar-cinomas and from neuroendocrine pancreatic tumors and review of the literature, Hell. J. Nucl. Med., 16, 97–102, doi: https://doi.org/10.1967/s002449910084.

    PubMed  Google Scholar 

  7. Warburg, O., Posener, K., and Negelein, E. (1924) Uber den stoffwechsel der karzinomzellen, Biochemische Zeitschrift, 152, 309–344.

    CAS  Google Scholar 

  8. Pavlides, S., Whitaker-Menezes, D., Castello-Cros, R., Flomenberg, N., Witkiewicz, A. K., Frank, P. G., Casimiro, M. C., Wang, C., Fortina, P., Addya, S., Pestell, R. G., Martinez-Outschoorn, U. E., Sotgia, F., and Lisanti, M. P. (2009) The reverse Warburg effect: aerobic glycolysis in cancer-associated fibroblasts and the tumor stroma, Cell Cycle, 8, 3984–4001.

    Article  CAS  PubMed  Google Scholar 

  9. Yingqian, L. V., Shan, Z., Jinzhu, H., Likang, Z., Zixin, Y., and Zhao, L. (2015) Hypoxia-inducible factor-1α induces multidrug resistance protein in colon cancer, Onco Targets Ther., 8, 1941–1948, doi: https://doi.org/10.2147/OTT.S82835.

    Google Scholar 

  10. Krasnov, G. S., Dmitriev, A. A., and Lakunina, V. A. (2013) Targeting VDAC-bound hexokinase II: a promising approach for concomitant anti-cancer therapy, Expert Opin. Ther. Targets, 17, 1221–1230, doi: https://doi.org/10.1517/14728222.2013.833607.

    Article  CAS  PubMed  Google Scholar 

  11. Mazumdar, J., Dondeti, V., and Simon, M. C. (2009) Hypoxia-inducible factors in stem cells and cancer, J. Cell. Mol. Med., 13, 4319–4328, doi: https://doi.org/10.1111/j.1582-4934.2009.00963.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Axelson, H., Fredlund, E., Ovenberger, M., Landberg, G., and Pahlman, S. (2005) Hypoxia-induced dedifferentiation of tumor cells - a mechanism behind heterogeneity and aggressiveness of solid tumors, Semin. Cell Dev. Biol., 16, 554–563.

    Article  CAS  PubMed  Google Scholar 

  13. Marin-Hernandez, A., Gallardo-Perez, J. C., Ralph, S. J., Rodriguez-Enriquez, S., and Moreno-Sanchez, R. (2009) HIF-1α modulates energy metabolism in cancer cells by inducing overexpression of specific glycolytic isoforms, Mini Rev. Med. Chem., 9, 1084–1101.

    Article  CAS  PubMed  Google Scholar 

  14. Lou, F., Chen, X., Jalink, M., Zhu, Q., Ge, N., Zhao, S., Fang, X., Fan, Y., Bjorkholm, M., Liu, Z., and Xu, D. (2007) The opposing effect of hypoxia-inducible factor-2α on expression of telomerase reverse transcriptase, Mol. Cancer Res., 5, 793–800.

    Article  CAS  PubMed  Google Scholar 

  15. Khromova, N. V., Kopnin, P. B., Stepanova, E. V., Agapova, L. S., and Kopnin, B. P. (2009) p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway, Cancer Lett., 276, 143–151, doi: https://doi.org/10.1016/j.canlet.2008.10.049.

    Article  CAS  PubMed  Google Scholar 

  16. Peng, X. H., Karna, P., Cao, Z., Jiang, B. H., Zhou, M., and Yang, L. (2006) Cross-talk between epidermal growth factor receptor and hypoxia-inducible factor-1alpha signal pathways increases resistance to apoptosis by up-regulating surviving gene expression, J. Biol. Chem., 281, 25903–25914.

    Article  CAS  PubMed  Google Scholar 

  17. Zhu, H., Wang, D., Liu, Y., Su, Z., Zhang, L., Chen, F., Zhou, Y., Wu, Y., Yu, M., Zhang, Z., and Shao, G. (2013) Role of the hypoxia-inducible factor-1alpha induced autophagy in the conversion of non-stem pancreatic cancer cells into CD133+ pancreatic cancer stem-like cells, Cancer Cell Int., 13, 119, doi: https://doi.org/10.1186/1475-2867-13-119.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Helczynska, K., Kronblad, A., Jogi, A., Nilsson, E., Beckman, S., and Landberg, G. (2003) Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ, Cancer Res., 63, 1441–1444.

    CAS  PubMed  Google Scholar 

  19. Shin, D. H., Dier, U., Melendez, J. A., and Hempel, N. (2015) Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells, Biochim. Biophys. Acta, 1852, 2593–2602.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Erler, J. T., and Giaccia, A. J. (2006) Lysyl oxidase mediates hypoxic control of metastasis, Cancer Res., 66, 10238–10241.

    Article  CAS  PubMed  Google Scholar 

  21. Kobliakov, V. A. (2017) Role of proton pumps in tumorigenesis, Biochemistry (Moscow), 82, 401–412, doi: https://doi.org/10.1134/S0006297917040010.

    Article  CAS  Google Scholar 

  22. Fukuda, R., Zhang, H., Kim, J. W., Shimoda, L., Dang, C. V., and Semenza, G. L. (2007) HIF-1 regulates cytochrome oxidase subunits to optimize efficiency of respiration in hypoxic cells, Cell, 129, 111–122.

    Article  CAS  PubMed  Google Scholar 

  23. Lee, K. A., Roth, R. A., and LaPres, J. J. (2007) Hypoxia, drug therapy and toxicity, Pharmacol. Ther., 113, 229–246, doi: https://doi.org/10.1016/j.pharmthera.2006.08.001.

    Article  CAS  Google Scholar 

  24. Berra, E., Benizri, E., Ginouves, A., Volmat, V., Roux, D., and Pouyssegur, J. (2003) HIF prolylhydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia, Embo J., 22, 4082–4090.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Selak, M. A., Armour, S. M., MacKenzie, E. D., Boulahbel, H., Watson, D. G., Mansfield, K. D., Pan, Y., Simon, M. C., Thompson, C. B., and Gottlieb, E. (2005) Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-alpha prolyl hydroxylase, Cancer Cell, 7, 77–85.

    Article  CAS  PubMed  Google Scholar 

  26. Chandel, N. S., McClintock, D. S., Feliciano, C. E., Wood, T. M., Melendez, J. A., Rodriguez, A. M., and Schumacker, P. T. (2000) Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing, J. Biol. Chem., 275, 25130–25138.

    Article  CAS  PubMed  Google Scholar 

  27. Lee, G., Won, H. S., Lee, Y. M., Choi, J. W., Oh, T. I., Jang, J. H., Choi, D. K., Lim, B. O., Kim, Y. J., Park, J. W., Puigserver, P., and Lim, J. H. (2016) Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation, Sci. Rep., 6, 18928, doi: https://doi.org/10.1038/srep18928.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Cash, T. P., Pan, Y., and Simon, M. C. (2007) Reactive oxygen species and cellular oxygen sensing, Free Radic. Biol. Med., 43, 1219–1225.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Chandel, N. S., Maltepe, E., Goldwasser, E., Mathieu, C. E., Simon, M. C., and Schumacker, P. T. (1998) Mitochondrial reactive oxygen species trigger hypoxia-induced transcription, Proc. Natl. Acad. Sci. USA, 95, 11715–11720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Mansfield, K. D., Guzy, R. D., Pan, Y., Young, R. M., Cash, T. P., Schumacker, P. T., and Simon, M. C. (2005) Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-alpha activation, Cell Metab., 1, 393–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Bell, E. L., Klimova, T. A., Eisenbart, J., Moraes, C. T., Murphy, M. P., Budinger, G. R., and Chandel, N. S. (2007) The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production, J. Cell Biol., 177, 1029–1036.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Henegan, J. C., Jr., and Gomez, C. R. (2016) Heritable cancer syndromes related to the hypoxia pathway, Front. Oncol., 6, 68, doi: https://doi.org/10.3389/fonc.2016.00068.

    Article  PubMed  PubMed Central  Google Scholar 

  33. Yang, H., and Kaelin, W. G., Jr. (2001) Molecular pathogenesis of the von Hippel-Lindau hereditary cancer syndrome: implications for oxygen sensing, Cell Growth Differ., 12, 447–455.

    CAS  PubMed  Google Scholar 

  34. hao, T., Mu, X., and You, Q. (2017) Succinate: an initiator in tumorigenesis and progression, Oncotarget, 8, 53819–53828, doi: https://doi.org/10.18632/oncotarget.17734.

    Google Scholar 

  35. Luo, W., Hu, H., Chang, R., Zhong, J., Knabel, M., O’Meally, R., Cole, R. N., Pandey, A., and Semenza, G. L. (2011) Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1, Cell, 145, 732–744.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. De Saedeleer, C. J., Copetti, T., Porporato, P. E., Verrax, J., Feron, O., and Sonveaux, P. (2012) Lactate activates HIF-1 in oxidative but not in Warburg-phenotype human tumor cells, PLoS One, 7, e46571, doi: https://doi.org/10.1371/journal.pone.0046571.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  37. Warfel, N. A., Dolloff, N. G., Dicker, D. T., Malysz, J., and El-Deiry, W. S. (2013) CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth, Cell Cycle, 12, 3689–3701.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Hubbi, M. E., Gilkesa, D. M., Hu, H., Ahmede, I., and Semenza, G. L. (2014) Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression, Proc. Natl. Acad. Sci. USA, 111, E3325–E3334.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Kietzmann, T. (2017) Metabolic zonation of the liver: the oxygen gradient revisited, Redox Biol., 11, 622–630.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Phan, A. T., and Goldrath, A. W. (2015) Hypoxia-inducible factors regulate T cell metabolism and function, Mol. Immunol., 68, 527–535, doi: https://doi.org/10.1016/j.molimm.2015.08.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Michalekand, R. D., and Rathmell, J. C. (2010) The metabolic life and times of a T-cell, Immunol. Rev., 236, 190–202, doi: https://doi.org/10.1111/j.1600-065X.2010.00911.x.

    Article  Google Scholar 

  42. Ohshima, H., Tatemichi, M., and Sawa, T. (2003) Chemical basis of inflammation-induced carcinogenesis, Arch. Biochem. Biophys., 417, 3–11.

    Article  CAS  PubMed  Google Scholar 

  43. Schwartsburd, P. M. (2003) Chronic inflammation as inductor of pro-cancer microenvironment: pathogenesis of dysregulated feedback control, Cancer Metastasis Rev., 22, 95–102.

    Article  CAS  PubMed  Google Scholar 

  44. Bokoch, G. M., and Knaus, U. G. (2003) NADPH oxidases: not just for leukocytes anymore! Trends Biochem. Sci., 28, 502–508.

    Article  CAS  PubMed  Google Scholar 

  45. Morry, J., Ngamcherdtraku, W., and Yantasee, W. (2017) Oxidative stress in cancer and fibrosis: opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles, Redox Biol., 11, 240–253, doi: https://doi.org/10.1016/j.redox.2016.12.011.

    Article  CAS  PubMed  Google Scholar 

  46. Balamurugan, K. (2016) HIF-1 at the crossroads of hypoxia, inflammation, and cancer, Int. J. Cancer, 138, 1058–1066.

    Article  CAS  PubMed  Google Scholar 

  47. Block, K., Gorin, Y., Hoover, P., Williams, P., Chelmicki, T., Clark, R. A., Yoneda, T., and Abboud, H. E. (2007) NAD(P)H oxidases regulate HIF-2alpha protein expression, J. Biol. Chem., 282, 8019–8026.

    Article  CAS  PubMed  Google Scholar 

  48. Juhasz, A., Markel, S., Gaur, S., Liu, H., Lu, J., Jiang, G., Wu, X., Antony, S., Wu, Y., Melillo, G., Meitzler, J. L., Haines, D. C., Butcher, D., Roy, K., and Doroshow, J. H. (2017) NADPH oxidase 1 supports proliferation of colon cancer cells by modulating reactive oxygen species-dependent signal transduction, J. Biol. Chem., 292, 7866–7887.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Antony, S., Jiang, G., Wu, Y., Meitzler, J. L., Makhlouf, H. R., Haines, D. C., Butcher, D., Hoon, D. S., Ji, J., Zhang, Y., Juhasz, A., Lu, J., Liu, H., Dahan, I., Konate, M., Roy, K. K., and Doroshow, J. H. (2017) NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates nor-moxic HIF-1α and p27Kip1 expression in malignant melanoma and other human tumors, Mol. Carcinog., 56, 2643–2662.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Skonieczna, M., Hejmo, T., Poterala-Hejmo, A., Cieslar-Pobuda, A., and Buldak, R. J. (2017) NADPH oxidases: insights into selected functions and mechanisms of action in cancer and stem cells, Oxid. Med. Cell. Longev., 2017, 9420539, doi: https://doi.org/10.1155/2017/9420539.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  51. Baeuerle, P. A., and Baltimore, D. (1996) NF-kappa B: ten years after, Cell, 87, 13–20.

    Article  CAS  PubMed  Google Scholar 

  52. D’Ignazio, L., Bandarra, D., and Rocha, S. (2016) NF-κB and HIF crosstalk in immune responses, FEBS J., 283, 413–424, doi: https://doi.org/10.1111/febs.13578.

    Article  PubMed  CAS  Google Scholar 

  53. Remels, A. H., Gosker, H. R., Verhees, K. J., Langen, R. C., and Schols, A. M. (2015) TNF-α-induced NF-κB activation stimulates skeletal muscle glycolytic metabolism through activation of HIF-1α, Endocrinology, 156, 1770–1781.

    Article  CAS  PubMed  Google Scholar 

  54. Pylayeva-Gupta, Y., Grabocka, E., and Bar-Sagi, D. (2011) RAS oncogenes: weaving a tumorigenic web, Nat. Rev. Cancer, 11, 761–774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Scheffzek, K., Ahmadian, M. R., Kabsch, W., Wiesmuller, L., Lautwein, A., Schmitz, F., and Wittinghofer, A. (1997) The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants, Science, 277, 333–338.

    Article  CAS  PubMed  Google Scholar 

  56. Bryant, K. L., Mancias, J. D., Kimmelman, A. C., and Der, C. J. (2014) KRAS: feeding pancreatic cancer proliferation, Trends Biochem. Sci., 39, 91–100, doi: https://doi.org/10.1016/j.tibs.2013.12.004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Hu, Y., Lu, W., Chen, G., Wang, P., Chen, Z., Zhou, Y., Ogasawara, M., Trachootham, D., Feng, L., and Pelicano, H. (2012) K-ras(G12V) transformation leads to mitochon-drial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis, Cell Res., 22, 399–412.

    Article  CAS  PubMed  Google Scholar 

  58. Chesney, J., and Telang, S. (2013) Regulation of glycolytic and mitochondrial metabolism by ras, Curr. Pharm. Biotechnol., 14, 251–260.

    Article  CAS  PubMed  Google Scholar 

  59. Irani, K., Xia, Y., Zweier, J. L., Sollott, S. J., Der, C. J., Fearon, E. R., Sundaresan, M., Finkel, T., and Goldschmidt-Clermont, P. J. (1997) Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts, Science, 275, 1649–1652.

    Article  CAS  PubMed  Google Scholar 

  60. Mitsushita, J., Lambeth, J. D., and Kamata, T. (2004) The superoxide-generating oxidase Nox1 is functionally required for Ras oncogene transformation, Cancer Res., 64, 3580–3585.

    Article  CAS  PubMed  Google Scholar 

  61. Komatsu, D., Kato, M., Nakayama, J., Miyagawa, S., and Kamata, T. (2008) NADPH oxidase 1 plays a critical mediating role in oncogenic Ras-induced vascular endothelial growth factor expression, Oncogene, 27, 4724–4732, doi: https://doi.org/10.1038/onc2008.102.

    Article  CAS  PubMed  Google Scholar 

  62. Qiu, R. G., Chen, J., Kirn, D., and Moon, A. (1995) An essential role for Rac in Ras transformation, Nature, 374, 457–459.

    Article  CAS  PubMed  Google Scholar 

  63. Kissil, J. L., Walmsley, M. J., Hanlon, L., Haigis, K. M., Bender Kim, C. F., Sweet-Cordero, A., Eckman, M. S., Tuveson, D. A., Capobianco, A. J., Tybulewicz, V. L., and Jacks, T. (2007) Requirement for Rac1 in a K-ras induced lung cancer in the mouse, Cancer Res., 67, 8089–8094.

    Article  CAS  PubMed  Google Scholar 

  64. Kazanietz, M. G., and Caloca, M. J. (2017) The Rac GTPase in cancer: from old concepts to new paradigms, Cancer Res., 77, 5445–5451.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Malliri, A., van Der Kammen, R. A., Clark, K., van der Valk, M., Michiels, F., and Collard, J. G. (2002) Mice deficient in the Rac activator Tiam1 are resistant to Rasinduced skin tumors, Nature, 417, 867–871.

    Article  CAS  PubMed  Google Scholar 

  66. Adachi, Y., Shibai, Y., Mitsushita, J., Shang, W. H., Hirose, K., and Kamata, T. (2008) Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6, Oncogene, 27, 4921–4932.

    Article  CAS  PubMed  Google Scholar 

  67. Wu, R. F., and Terada, L. S. (2009) Ras and Nox: linked signaling networks? Free Radic. Biol. Med., 47, 1276–1281, doi: https://doi.org/10.1016/j.freeradbiomed.2009.05.037.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Neuzil, J., Rohlena, J., and Dong, L. F. (2012) K-Ras and mitochondria: dangerous liaisons, Cell Res., 22, 285–287, doi: https://doi.org/10.1038/cr.2011.160.

    Article  CAS  PubMed  Google Scholar 

  69. Weinberg, F., Hamanaka, R., Wheaton, W. W., Weinberg, S., Joseph, J., Lopez, M., Kalyanaraman, B., Mutlu, G. M., Budinger, G. R., and Chandel, N. S. (2010) Mitochondrial metabolism and ROS generation are essential for K-ras-mediated tumorigenicity, Proc. Natl. Acad. Sci. USA, 107, 8788–8793.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Martin, T. D., Cook, D. R., Choi, M. Y., Li, M. Z., Haigis, K. M., and Elledge, S. J. (2017) Role for mitochondrial translation in promotion of viability in K-Ras mutant cells, Cell Rep., 20, 427–438.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Heit, B., Yeung, T., and Grinstein, S. (2011) Changes in mitochondrial surface charge mediate recruitment of signaling molecules during apoptosis, Am. J. Physiol. Cell. Physiol., 300, C33–C41.

    Article  CAS  PubMed  Google Scholar 

  72. Irby, R. B., and Yeatman, T. J. (2000) Role of Src expression and activation in human cancer, Oncogene, 19, 5636–5642.

    Article  CAS  PubMed  Google Scholar 

  73. Siveen, K. S., Prabhu, K. S., Achkar, I. W., Kuttikrishnan, S., Shyam, S., Khan, A. Q., Merhi, M., Dermime, S., and Uddin, S. (2018) Role of non-receptor tyrosine kinases in hematological malignances and its targeting by natural products, Mol. Cancer, 17, 31, doi: https://doi.org/10.1186/s12943-018-0788-y.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Carroll, R. C., Ash, J. F., Vogt, P. K., and Singer, S. J. (1978) Reversion of transformed glycolysis to normal by inhibition of protein synthesis in rat kidney cells infected with temperature-sensitive mutant of Rous sarcoma virus, Proc. Natl. Acad. Sci. USA, 75, 5015–5019.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Lee, H. Y., Lee, T., and Lee, N. (2011) Src activates HIF1α not through direct phosphorylation of HIF1α specific prolyl-4 hydroxylase 2 but through activation of the NADPH oxidase/Rac pathway, Carcinogenesis, 32, 703–712.

    Article  CAS  PubMed  Google Scholar 

  76. Jin, Y., Cai, Q., Shenoy, A. K., Lim, S., Zhang, Y., Charles, S., Tarrash, M., Fu, X., Kamarajugadda, S., Trevino, J. G., Tan, M., and Lu, J. (2016) Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation, Oncotarget, 7, 25113–25124.

    PubMed  PubMed Central  Google Scholar 

  77. Chou, M. T., Anthony, J., Bjorge, J. D., and Fujita, D. J. (2010) The von Hippel-Lindau tumor suppressor protein is destabilized by Src: implications for tumor angiogenesis and progression, Genes Cancer, 1, 225–238.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Vettori, A., Greenald, D., Wilson, G. K., Peron, M., Facchinello, N., Markham, E., Sinnakaruppan, M., Matthews, L. C., McKeating, J. A., Argenton, F., and van Eeden, F. J. M. (2017) Glucocorticoids promote Von Hippel-Lindau degradation and Hif1α stabilization, Proc. Natl. Acad. Sci. USA, 114, 9948–9953.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  79. Leontieva, O. V., Demidenko, Z. N., and Blagosklonny, M. V. (2015) Dual mTORC1/C2 inhibitors suppress cellular geroconversion (a senescence program), Oncotarget, 6, 23238–23248.

    Article  PubMed  PubMed Central  Google Scholar 

  80. Leontieva, O. V., and Blagosklonny, M. V. (2014) M-TOR of pseudo-hypoxic state in aging: rapamycin to the rescue, Cell Cycle, 13, 509–515.

    Article  CAS  PubMed  Google Scholar 

  81. Sato, T., Nakashima, A., Guo, L., Coffman, K., and Tamanoi, F. (2010) Single amino-acid changes that confer constitutive activation of mTOR are discovered in human cancer, Oncogene, 29, 2746–2752.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Grabiner, B. C., Nardi, V., Birsoy, K., Possemato, R., Shen, K., Sinha, S., Jordan, A., Beck, A. H., and Sabatini, D. M. (2014) A diverse array of cancer-associated mTOR mutations are hyperactivating and can predict rapamycin sensitivity, Cancer Discov., 4, 554–563.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Blagosklonny, M. V. (2008) Prevention of cancer by inhibiting aging, Cancer Biol. Ther., 7, 1520–1524.

    Article  CAS  PubMed  Google Scholar 

  84. Ma, X. M., and Blenis, J. (2009) Molecular mechanisms of mTOR-mediated translational control, Nat. Rev. Mol. Cell Biol., 10, 307–318, doi: https://doi.org/10.1038/nrm2672.

    Article  PubMed  CAS  Google Scholar 

  85. Busch, S., Renaud, S. J., Schleussner, E., Graham, C. H., and Markert, U. R. (2009) mTOR mediates human trophoblast invasion through regulation of matrix-remodeling enzymes and is associated with serine phosphorylation of STAT3, Exp. Cell Res., 315, 1724–1733, doi: https://doi.org/10.1016/j.yexcr.2009.01.026.

    Article  CAS  PubMed  Google Scholar 

  86. Dodd, K., Yang, J., Shen, M., Sampson, J., and Tee, A. (2015) mTORC1 drives HIF-1α and VEGF-A signaling via multiple mechanisms involving 4E-BP1, S6K1 and STAT3, Oncogene, 34, 2239–2250.

    Article  CAS  PubMed  Google Scholar 

  87. Gao, P., Niu, N., Wei, T., Tozawa, H., Chen, X., Zhang, C., Zhang, J., Wada, Y., Kapron, C. M., and Liu, J. (2017) The roles of signal transducer and activator of transcription factor 3 in tumor angiogenesis, Oncotarget, 8, 69139–69161.

    PubMed  PubMed Central  Google Scholar 

  88. Shaw, R. J. (2009) LKB1 and AMP-activated protein kinase control of mTOR signaling and growth, Acta Physiol. (Oxf.), 196, 65–80.

    Article  CAS  Google Scholar 

  89. Kim, I. Y., and Yu-Ying, H. (2013) Targeting the AMP-activated protein kinase for cancer prevention and therapy, Front. Oncol., 3, 175, doi: https://doi.org/10.3389/fonc.2013.00175.

    PubMed  PubMed Central  Google Scholar 

  90. Faubert, B., Boily, G., Izreig, S., Griss, T., Samborska, B., Dong, Z., Dupuy, F., Chambers, C., Fuerth, B. J., Viollet, B., Mamer, O. A., Avizonis, D., DeBerardinis, R. J., Siegel, P. M., and Jones, R. G. (2013) AMPK is a negative regulator of the Warburg effect and suppresses tumor growth in vivo, Cell Metab., 17, 113–124.

    Article  CAS  PubMed  Google Scholar 

  91. Schmelzle, T., and Hall, M. (2000) TOR, a central controller, Cell, 103, 253–262.

    Article  CAS  PubMed  Google Scholar 

  92. Kim, E. K., Yun, S. J., Ha, J. M., Kim, Y. W., Jin, I. H., Yun, J., Shin, H. K., Song, S. H., Kim, J. H., Lee, J. S., Kim, C. D., and Bae, S. S. (2011) Selective activation of Akt1 by mammalian target of rapamycin complex 2 regulates cancer cell migration, invasion, and metastasis, Oncogene, 30, 2954–2963.

    Article  CAS  PubMed  Google Scholar 

  93. Prendergast, G. C. (1999) Mechanisms of apoptosis by c-Myc, Oncogene, 18, 2967–2987.

    Article  CAS  PubMed  Google Scholar 

  94. Yoshida, G. J. (2018) Emerging roles of Myc in stem cell biology and novel tumor therapies, J. Exp. Clin. Cancer Res., 37, 173, doi: https://doi.org/10.1186/s13046-018-0835-y.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  95. Wahlstrom, T., and Henriksson, M. A. (2015) Impact of MYC in regulation of tumor cell metabolism, Biochim. Biophys. Acta, 1849, 563–569.

    Article  PubMed  CAS  Google Scholar 

  96. Kalkat, M., De Melo, J., Hickman, K. A., Lourenco, C., Redel, C., Resetca, D., Tamachi, A., Tu, W. B., and Penn, L. Z. (2017) MYC deregulation in primary human cancers, Genes (Basel), 8, E151, doi: https://doi.org/10.3390/genes8060151.

    Article  CAS  Google Scholar 

  97. Schaub, F. X., Dhankani, V., Berger, A. C., Trivedi, M., Richardson, A. B., Shaw, R., Zhao, W., Zhang, X., Ventura, A., Liu, Y., Ayer, D. E., Hurlin, P. J., Cherniack, A. D., Eisenman, R. N., Bernard, B., and Grandori, C. (2018) Pan-cancer alterations of the MYC oncogene and its proximal network across the cancer genome atlas, Cell Syst., 6, 282–300.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  98. Dang, C. V. (2012) MYC on the path to cancer, Cell, 149, 22–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Osthus, R. C., Shim, H., Kim, S., Li, Q., Reddy, R., Mukherjee, M., Xu, Y., Wonsey, D., Lee, L. A., and Dang, C. V. (2000) Deregulation of glucose transporter 1 and glycolytic gene expression by c-Myc, J. Biol. Chem., 275, 21797–21800.

    Article  CAS  PubMed  Google Scholar 

  100. He, T. L., Zhang, Y. J., Jiang, H., Li, X. H., Zhu, H., and Zheng, K. L. (2015) The c-Myc-LDHA axis positively regulates aerobic glycolysis and promotes tumor progression in pancreatic cancer, Med. Oncol., 32, 187, doi: https://doi.org/10.1007/s12032-015-0633-8.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Kim, J. W., Gao, P., Liu, Y. C., Semenza, G. L., and Dang, C. V. (2007) Hypoxia-inducible factor 1 and dysregulated c-Myc cooperatively induce vascular endothelial growth factor and metabolic switches hexokinase 2 and pyruvate dehydrogenase kinase 1, Mol. Cell. Biol., 27, 7381–7393.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zarrabi, A. J., Kao, D., Nguyen, D. T., Loscalzo, J., and Handy D. E. (2017) Hypoxia-induced suppression of c-Myc by HIF-2α in human pulmonary endothelial cells attenuates TFAM expression, Cell. Signal., 38, 230–237.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Huang, L. E. (2008) Carrot and stick: HIF-alpha engages c-Myc in hypoxic adaptation, Cell Death Differ., 15, 672–677, doi: https://doi.org/10.1038/sj.cdd.4402302.

    Article  CAS  PubMed  Google Scholar 

  104. Goda, N., Ryan, H. E., Khadivi, B., McNulty, W., Rickert, R. C., and Johnson, R. S. (2003) Hypoxia-inducible factor 1alpha is essential for cell cycle arrest during hypoxia, Mol. Cell. Biol., 23, 359–369.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Koshiji, M., Kageyama, Y., Pete, E. A., Horikawa, I., Barrett, J. C., and Huang, L. E. (2004) HIF-1alpha induces cell cycle arrest by functionally counteracting Myc, EMBO J., 23, 1949–1956.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Wang, L., Xue, M., and Chung, D. C. (2016) c-Myc is regulated by HIF-2α in chronic hypoxia and influences sensitivity to 5-FU in colon cancer, Oncotarget, 7, 78910–78917.

    PubMed  PubMed Central  Google Scholar 

  107. Dang, C. V., Kim, J. W., Gao, P., and Yustein, J. (2008) The interplay between MYC and HIF in cancer, Nat. Rev. Cancer, 8, 51–56.

    Article  CAS  PubMed  Google Scholar 

  108. Zhou, Q., Jin, P., Liu, J., Wang, F., and Xi, S. (2018) HER2 and Src co-regulate proliferation, migration and transformation by downstream signaling pathways in arsenite-treated human uroepithelial cells, Metallomics, 10, 1141–1159.

    Article  CAS  PubMed  Google Scholar 

  109. Wang, L. H., Jiang, X. R., Yang, J. Y., Bao, X. F., Chen, J. L., Liu, X., Chen, G. L., and Wu, C. F. (2016) SYP-5, a novel HIF1 inhibitor, suppresses tumor cells invasion and angiogenesis, Eur. J. Pharmacol., 791, 560–568.

    Article  CAS  PubMed  Google Scholar 

  110. Niu, W., Luo, Y., Wang, X., Zhou, Y., Li, H., Wang, H., Fu, Y., Liu, S., Yin, S., Li, J., Zhao, R., Liu, Y., Fan, S., Li, Z., Xiong, W., Li, X., Li, G., Ren, C., Tan, M., and Zhou, M. (2018) BRD7 inhibits the Warburg effect and tumor progression through inactivation of HIF1α/LDHA axis in breast cancer, Cell Death Dis., 9, 519, doi: https://doi.org/10.1038/s41419-018-0536-7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  111. Semenza, G. L. (2009) Regulation of cancer cell metabolism by hypoxia-inducible factor 1, Seminars in Cancer Biology, 19, 12–16.

    Article  CAS  PubMed  Google Scholar 

  112. Masoud, G. N., and Li, W. (2015) HIF-1α pathway: role, regulation and intervention for cancer therapy, Acta Pharm. Sin. B, 5, 378-389, doi: https://doi.org/10.1016/j.apsb.2015.05.007.

    Article  PubMed  PubMed Central  Google Scholar 

  113. Park, K., Lee, H. E., Lee, S. H., Lee, D., Lee, T., and Lee, Y. M. (2017) Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound, Oncotarget, 8, 7801–7813.

    PubMed  Google Scholar 

  114. Masoud, G. N., Wang, J., Chen, J., Miller, D., and Li, W. (2015) Design, synthesis and biological evaluation of novel HIF1α inhibitors, Anticancer Res., 35, 3849–3859.

    CAS  PubMed  PubMed Central  Google Scholar 

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Funding

The work was carried out and financed within the budgetary project “Genotoxic action of chemotherapeutical preparations on medical staff during the treatment of oncology patients” (AAAA-A19-119031390107-7).

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  1. Blokhin Cancer Research Center, Ministry of Health of Russia, 115478, Moscow, Russia

    V. A. Kobliakov

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Russian Text © The Author(s), 2019, published in Biokhimiya, 2019, Vol. 84, No. 10, pp. 1371-1384.

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Kobliakov, V.A. The Mechanisms of Regulation of Aerobic Glycolysis (Warburg Effect) by Oncoproteins in Carcinogenesis. Biochemistry Moscow 84, 1117–1128 (2019). https://doi.org/10.1134/S0006297919100018

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