HIFα как объект воздействия различных онкобелков при канцерогенезе

Основные свойства злокачественности – инвазия и метастазирование – реализуются благодаря разрушению межклеточного матрикса. В этом процессе принимают участие металлопротеазы, активация которых вызвана подкислением межклеточного пространства, обусловленного переходом опухолевых клеток с тканевого дыхания на гликолиз. Переключение на гликолиз в опухолевых клетках происходит не только в условиях гипоксии, что наблюдается и в нормальной ткани, но и при оксигенации (эффект Варбурга). Считается, что в процессе канцерогенеза происходит активация онкогенов и / или дезактивация генов-супрессоров, вызывающие в конечном итоге развитие опухоли. Трансформация и последующая пролиферация клеток опосредована функциональным действием целого ряда онкобелков, являющихся компонентами различных регуляторных сигнальных цепей. Можно предположить, что онкобелки не всегда конечные факторы, вызывающие развитие опухолевого процесса, а конечным звеном является некий общий для всех канцерогенных воздействий элемент, активируемый различными онкогенами.

В данном обзоре обсуждается возможность того, что при функционировании многих онкогенных факторов таким звеном является транскрипционный фактор HIFα (hypoxia-inducible factor α), и рассматриваются механизмы его активации при действии онкогенов, участвующих в регуляции различных сигнальных систем.

канцерогенез, гипоксия, эффект Варбурга, транскрипционный фактор HIFα, воспаление, ras, src

1. Estrella V., Chen T., Lloyd M. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 2013;73(3):1524—35. DOI: 10.1158/0008-5472.CAN-12-2796. PMID: 23288510.

2. McCarty M.F., Whitaker J. Manipulating tumor acidification as a cancer treatment strategy Altern Med Rev 2010;15(3): 264-72. PMID: 21155627.

3. Martin N.K., Robey I.F., Gaffney E.A. et al. Predicting the safety and efficacy of buffer therapy to raise tumour pHe: an integrative modelling study. Br J Cancer 2012;106(7):1280—7. DOI: 10.1038/bjc.2012.58. PMID: 22382688.

4. Fais S., Venturi G., Gatenby B. Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy. Cancer Metastasis Rev 2014;33(4):1095—108. DOI: 10.1007/s10555-014-9534-0. PMID: 25430903.

5. Harguindey S., Arranz J.L., Polo Orozco J.D. et al. 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. Transl Med 2013;11:282. DOI: 10.1186/1479-5876-11-282. PMID: 24195657.

6. Guan Z.W., Xu B.X., Wang R.M. et al. Hyperaccumulation of (18)F-FDG in order to differentiate solid pseudopapillary tumors from adenocarcinomas and from neuroendocrine pancreatic tumors and review of the literature. Hell J Nucl Med 2013;16(2):97—102. DOI: 10.1967/s002449910084. PMID: 23687644.

7. Schlaepfer I.R., Glode L.M., Hitz C.A. et al. Inhibition of lipid oxidation increases glucose metabolism and enhances 2-de-oxy-2-[(18)F]fluoro-D-glucose uptake in prostate cancer mouse xenografts. Mol Imaging Biol 2015;17(4):529—38. DOI: 10.1007/s11307-014-0814-4. PMID: 25561013.

8. Warburg O., Posener K., Negelein E. Uber den Stoffwechsel der Karzinomzellen. Biochemische Zeitschrift 1924;152: 309—44.

9. Lu H., Forbes R.A., Verma A. Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis J Biol Chem 2002;277(26):23111—5. DOI: 10.1074/jbc.M202487200. PMID: 11943784.

10. Marin-Hernandez A., Gallardo-Perez J.C., Ralph S.J. et al. HIF-1alpha modulates energy metabolism in cancer cells by inducing over-expression of specific glycolytic isoforms. Mini Rev Med Chem 2009;9(9):1084—101. PMID: 19689405.

11. Lou F., Chen X., Jalink M. et al. The opposing effect of hypoxia-inducible factor-2alpha on expression of telomerase reverse transcriptase. Mol Cancer Res 2007;5(8):793—800. DOI: 10.1158/1541-7786.MCR-07-0065. PMID: 17699105.

12. Yatabe N., Kyo S., Maida Y. et al. HIF-1-mediated activation of telomerase in cervical cancer cells. Oncogene 2004;23(20):3708—15. DOI: 10.1038/sj.onc.1207460. PMID: 15048086.

13. Wang M., Kirk J.S., Venkataraman S. et al. Manganese superoxide dismutase suppresses hypoxic induction of hypoxia-inducible factor-1alpha and vascular endothelial growth factor. Oncogene 2005;24(55):8154—66. DOI: 10.1038/sj.onc.1208986. PMID: 16170370.

14. Jeon H., Kim H., Choi D. et al. Quercetin activates an angiogenic pathway HIF-1-VEGF by inhibiting HIF-prolyl hydroxylase: a structural analysis of quercetin for inhibiting HIF-prolyl hydroxylase. Mol Pharmacol 2007;71(6):1676—84. DOI: 10.1124/mol.107.034041. PMID: 17377063.

15. Khromova N.V., Kopnin P.B., Stepanova E.V. et al. p53 hot-spot mutants increase tumor vascularization via ROS-mediated activation of the HIF1/VEGF-A pathway. Cancer Lett 2009;276(2):143— 51. DOI: 10.1016/j.canlet.2008.10.049. PMID: 19091459.

16. Peng X.H., Kama P., Cao Z. et al. Crosstalk between epidermal growth factor receptor and hypoxia-inducible factor-1al-pha signal pathways increases resistance to apoptosis by up-regulating survivin gene expression. J Biol Chem 2006;281(36):25903—14. DOI: 10.1074/jbc.M603414200. PMID: 16847054.

17. Liu X.H., Yu E.Z., Li Y.Y., Kagan E. HIF-1alpha has an anti-apoptotic effect in human airway epithelium that is mediated via Mcl-1 gene expression. J Cell Bio-chem 2006;97(4):755—6. DOI: 10.1002/jcb.20683. PMID: 16229017.

18. Rankin E.B., Giaccia A.J. The role of hy-2 poxia-inducible factors in tumorigenesis. Cell Death Differ 2008;15(4):678—85. DOI: 10.1038/cdd.2008.21. PMID: 18259193.

19. Axelson H., Fredlund E., Ovenberger M. 2 et al. Hypoxia-induced dedifferentiation of tumor cells — a mechanism behind heterogeneity and aggressiveness of solid tumors. Semin Cell Dev Biol 2005; 16(4—5):554—63. DOI: 10.1016/j.semcdb.2005.03.007. PMID: 16144692.

20. Helczynska K., Kronblad A., Jogi A. et al. Hypoxia promotes a dedifferentiated phenotype in ductal breast carcinoma in situ. Cancer Res 2003;63(7):1441—4. PMID: 12670886.

21. Shin D.H., Dier U., Melendez J.A., Hem-pel N. Regulation of MMP-1 expression in response to hypoxia is dependent on the intracellular redox status of metastatic bladder cancer cells. Biochim Bio-phys Acta 2015;1852(12):2593—602. DOI: 10.1016/j.bbadis.2015.09.001. PMID: 26343184.

22. Lv Y., Zhao S., Han J. et al. Hypoxia-inducible factor-1a induces multidrug resistance protein in colon cancer. Onco Targets Ther 2015;8:1941-8. DOI: 10.2147/OTT.S82835. PMID: 26251616.

23. Erler J.T., Giaccia A.J. Lysyl oxidase mediates hypoxic control of metastasis. Cancer Res 2006;66(21):10238-41. DOI: 10.1158/0008-5472.CAN-06-3197. PMID: 17079439.

24. Kobliakov V.A. Role of proton pumps in tumorigenesis. Biochemistry (Moscow) 2017;82(4):401 —12. DOI: 10.1134/ S0006297917040010. PMID: 28371597.

25. Lee K.A., Roth R.A., LaPres J.J. Hypoxia, drug therapy and toxicity. Pharmacol. Ther 2007;13(2):229—63. DOI: 10.1016/j.phar-mthera.2006.08.001. PMID: 17046066.

26. Cash T.P., Pan Y., Simon M.C. Reactive oxygen species and cellular oxygen sensing. Free Radic Biol Med 2007;43(9):1219—25. DOI: 10.1016/j.fre-eradbiomed.2007.07.001. PMID: 17893032.

27. Place T.L. Domann F.E. Prolyl-hydroxylase 3: evolving roles for an ancient signaling protein. Hypoxia 2013:13(1):13—27. DOI: 10.2147/HP.S50091. PMID: 24672806.

28. Berra E., Benizri E., Ginouves A. et al. HIF prolyl-hydroxylase 2 is the key oxygen sensor setting low steady-state levels of HIF-1alpha in normoxia. Embo J 2003;22(16):4082—90. DOI: 10.1093/emboj/cdg392. PMID: 12912907.

29. Selak M.A., Armour S.M., MacKenzie E.D. et al. Succinate links TCA cycle dysfunction to oncogenesis by inhibiting HIF-al-pha prolyl hydroxylase. Cancer Cell 2005;7(1):77—85. DOI: 10.1016/j.ccr.2004.11.022. PMID: 15652751.

30. Chandel N.S., McClintock D.S., Feliciano C.E. et al. Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing. J Biol Chem 2000;275(33):25130—8. DOI: 10.1074/jbc.M001914200. PMID: 10833514.

31. Lee G., Won H.S., Lee Y.M. et al. Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1a activation. Sci Rep 2016;6:18928. DOI: 10.1038/srep18928. PMID: 26740011.

32. Chandel N.S., Maltepe E., Goldwasser E. et al. Mitochondrial reactive oxygen species trigger hypoxiainduced transcription. Proc Natl Acad Sci USA 1998;95(20):11715—20. PMID: 9751731.

33. Mansfield K.D., Guzy R.D., Pan Y. et al. Mitochondrial dysfunction resulting from loss of cytochrome c impairs cellular oxygen sensing and hypoxic HIF-a activation. Cell Metab 2005;1(6):393—9. DOI: 10.1016/j.cmet.2005.05.003. PMID: 16054088.

34. Bell E.L., Klimova T.A., Eisenbart J. et al. The Qo site of the mitochondrial complex III is required for the transduction of hypoxic signaling via reactive oxygen species production. J Cell Biol 2007;177(6): 1029—36. DOI: 10.1083/jcb.200609074. PMID: 17562787.

35. Guzy R.D., Schumacker P.T. Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia. Exp Physiol 2006;91(5):807—19. DOI: 10.1113/expphysiol.2006.033506. PMID: 16857720.

36. Henegan J.C. Jr, Gomez C.R. Heritable cancer syndromes related to the hypoxia pathway. Front Oncol 2016;6:68. DOI: 10.3389/fonc.2016.00068. PMID: 27047799.

37. Yang H., Kaelin W.G. Jr. Molecular pathogenesis of the von Hippel—Lindau hereditary cancer syndrome: implications for oxygen sensing. Cell Growth Differ 2001;12(9):447— 55. PMID: 11571227.

38. Luo W., Hu H., Chang R. et al. Pyruvate kinase M2 is a PHD3-stimulated coactivator for hypoxia-inducible factor 1. Cell 2011;145(5):732—44. DOI: 10.1016/j.cell.2011.03.054. PMID: 21620138.

39. Colegio O.R. Lactic acid polarizes macrophages to a tumor-promoting state. Onco-immunology 2015;5(3):e1014774. DOI: 10.1080/2162402X.2015.1014774. PMID: 27141329.

40. Colegio O.R., Chu N.Q., Szabo A.L. et al. Functional polarization of tumour-associ-ated macrophages by tumourderived lactic acid. Nature 2014;513(7519):559—63. DOI: 10.1038/nature13490. PMID: 25043024.

41. Ohshima H., Tatemichi M., Sawa T. Chemical basis of inflammation-induced carcinogenesis. Arch Biochem Biophys 2003;417(1):3—11. PMID: 12921773.

42. Schwartsburd P.M. Chronic inflammation as inductor of pro-cancer microenvironment: pathogenesis of dysregulated feedback control. Cancer Metastasis Rev 2003;22(1):95—102. PMID: 12716041.

43. Morry J., Ngamcherdtrakul W., Yantasee W. Oxidative stress in cancer and fibrosis: opportunity for therapeutic intervention with antioxidant compounds, enzymes, and nanoparticles. Redox Biol 2017;11:240—53. DOI: 10.1016/j.re-dox.2016.12.011. PMID: 28012439.

44. Bokoch G.M., Knaus U.G. NADPH oxidases: not just for leukocytes anymore! Trends Biochem Sci 2003;28(9):502—8. DOI: 10.1016/S0968-0004(03)00194-4. PMID: 13678962.

45. Balamurugan K. HIF-1 at the crossroads of hypoxia, inflammation, and cancer. Int J Cancer 2016;138(5):1058—66. DOI: 10.1002/ijc.29519. PMID: 25784597.

46. Block K., Gorin Y., Hoover P. et al. NAD(P)H oxidases regulate HIF-2alpha protein expression. J Biol Chem 2007;282(11):8019—26. DOI: 10.1074/jbc.M611569200. PMID: 17200123.

47. Juhasz A., Markel S., Gaur S. et al. NADPH oxidase 1 supports proliferation of colon cancer cells by modulating reactive oxygen species-dependent signal transduction. J Biol Chem 2017;292(19):7866—87. DOI: 10.1074/jbc. M116.768283. PMID: 28330872.

48. Antony S., Jiang G., Wu Y. et al. NADPH oxidase 5 (NOX5)-induced reactive oxygen signaling modulates normoxic HIF-1a and p27Kip1 expression in malignant melanoma and other human tumors. Mol Car-cinog 2017;56(12):2643—62. DOI: 10.1002/mc.22708. PMID: 28762556.

49. Lambeth J.D. Nox enzymes, ROS, and chronic disease: an example of antagonistic pleiotropy. Free Radic Biol Med 2007;43(3):332—47. DOI: 10.1016/j.fre-eradbiomed.2007.03.027. PMID: 17602948.

50. Skonieczna M., Hejmo T., Poterala-Hej-mo A. et al. NADPH oxidases: insights into selected functions and mechanisms of action in cancer and stem cells. Oxid Med Cell Longev 2017;2017:9420539. DOI: 10.1155/2017/9420539. PMID: 28626501.

51. Baeuerle P.A., Baltimore D. NF-kappa B: ten years after. Cell 1996;87(1):13—20. PMID: 8858144.

52. D’Ignazio L., Bandarra D., Rocha S. NF-kB and HIF crosstalk in immune responses. FEBS J 2016;283(3):413—24. DOI: 10.1111/febs.13578. PMID: 26513405.

53. Remels A.H., Gosker H.R., Verhees K.J. et al. TNF-a-induced NF-kB activation stimulates skeletal muscle glycolytic metabolism through activation of HIF-1a. Endocrinology 2015;156(5):1770—81. DOI: 10.1210/en.2014-1591. PMID: 25710281.

54. Pylayeva-Gupta Y., Grabocka E., Bar-Sagi D. RAS oncogenes: weaving a tumongenic web. Nat Rev Cancer. 2011;11(11):761—74.

55. Scheffzek K., Ahmadian M.R., Kabsch W. et al. The Ras-RasGAP complex: structural basis for GTPase activation and its loss in oncogenic Ras mutants. Science 1997;277(5324):333—8. PMID: 9219684.

56. Bryant K.L., Mancias J.D., Kimmel-man A.C., Der C.J. KRAS: feeding pancreatic cancer proliferation. Trends Bio-chem Sci 2014;39(2):91—100. DOI: 10.1016/j.tibs.2013.12.004. PMID: 24388967.

57. Hu Y., Lu W., Chen G. et al. K-ras(G12V) transformation leads to mitochondrial dysfunction and a metabolic switch from oxidative phosphorylation to glycolysis. Cell Res 2012;22(2):399—412. DOI: 10.1038/cr.2011.145. PMID: 21876558.

58. Chesney J., Telang S. Regulation of glycolytic and mitochondrial metabolism by ras. Curr Pharm Biotechnol 2013;14(3): 251-60. PMID: 22201601.

59. Irani K., Xia Y., Zweier J.L. et al. Mitogenic signaling mediated by oxidants in Ras-transformed fibroblasts. Science 1997;275(5306):1649—52. PMID: 9054359.

60. Mitsushita J., Lambeth J.D., Kamata T. The superoxidegenerating oxidase Nox1 is functionally required for Ras oncogene transformation. Cancer Res 2004;64(10):3580—5. DOI: 10.1158/0008-5472.CAN-03-3909. PMID: 15150115.

61. Shin I., Kim S., Song H. et al. H-Ras-spe-cific activation of Rac-MKK3/6-p38 pathway: its critical role in invasion and migration of breast epithelial cells. J Biol Chem 2005;280(15):14675—83. DOI: 10.1074/jbc.M411625200. PMID: 15677464.

62. Qiu R.G., Chen J., Kirn D. et al. An essential role for Rac in Ras transformation. Nature 1995;374(6521):457—9. DOI: 10.1038/374457a0. PMID: 7700355.

63. Kissil J.L., Walmsley M.J., Hanlon L. et al. Requirement for Rac1 in a K-ras induced lung cancer in the mouse. Cancer Res 2007;67(17):8089—94. DOI: 10.1158/0008-5472.CAN-07-2300. PMID: 17804720.

64. Kazanietz M.G., Caloca M.J. The Rac GTPase in cancer: from old concepts to new paradigms. Cancer Res 2017;77(20):5445—51. DOI: 10.1158/0008-5472.CAN-17-1456. PMID: 28807941.

65. Malliri A., van Der Kammen R.A., Clark K. et al. Mice deficient in the Rac activator Tiam1 are resistant to Ras-induced skin tumours. Nature 2002;417(6891):867—71. DOI: 10.1038/nature00848. PMID: 12075356.

66. Adachi Y., Shibai Y., Mitsushita J. et al. Oncogenic Ras upregulates NADPH oxidase 1 gene expression through MEK-ERK-dependent phosphorylation of GATA-6. Oncogene 2008;27(36):4921— 32. DOI: 10.1038/onc.2008.133. PMID: 18454176.

67. Wu R.F., Terada L.S. Ras and Nox: linked signaling networks? Free Radic Biol Med 2009;47(9):1276—81. DOI: 10.1016/j.fre-eradbiomed.2009.05.037. PMID: 19501154.

68. Neuzil J., Rohlena J., Dong L.F. K-Ras and mitochondria: dangerous liaisons. Cell Res 2012;22(2):285—7. DOI: 10.1038/cr.2011.160. PMID: 21946499.

69. Weinberg F., Hamanaka R., Wheaton W.W. et al. Mitochondrial metabolism and ROS generation are essential for K-ras-mediat-ed tumorigenicity. Proc Natl Acad Sci USA 2010;107(19):8788—93. DOI: 10.1073/pnas.1003428107. PMID: 20421486.

70. Martin T.D., Cook D.R., Choi M.Y. et al. Role for mitochondrial translation in promotion of viability in K-Ras mutant cells. Cell Rep 2017;20(2):427—38. DOI: 10.1016/j.celrep.2017.06.061. PMID: 28700943.

71. Irby R.B., Yeatman T.J. Role of Src expression and activation in human cancer. Oncogene 2000;19(49):5636—42. DOI: 10.1038/sj.onc.1203912. PMID: 11114744.

72. Siveen K.S., Prabhu K.S., Achkar I.W. et al. Role of non receptor tyrosine kinases in hematological malignances and its targeting by natural products. Mol Cancer 2018;17(1):31. DOI: 10.1186/s12943-018-0788-y. PMID: 29455667.

73. Carroll R.C., Ash J.F., Vogt P.K., Singer S.J. 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 1978;75(10);5015—9. PMID: 217010.

74. Lee H.Y., Lee T., Lee N. et al. Src activates HIF1a not through direct phosphorylation of HIF1a specific prolyl-4 hydroxylase 2 but through activation of the NADPH oxi-dase/Rac pathway. Carcinogenesis 2011;32(5):703—12.

75. Jin Y., Cai Q., Shenoy A.K. et al. Src drives the Warburg effect and therapy resistance by inactivating pyruvate dehydrogenase through tyrosine-289 phosphorylation. Oncotarget 2016;7(18):25113—24. DOI: 10.18632/oncotarget.7159. PMID: 26848621.

76. Chou M.T., Anthony J., Bjorge J.D., Fu-jita D.J. The von Hippel—Lindau tumor supressor protein is destabilized by Src: implications for tumor angiogenesis and progression. Genes Cancer 2010;1(3):225—38. DOI: 10.1177/1947601910366719. PMID: 21212839.

77. Vettori A., Greenald D., Wilson G.K. et al. Glucocorticoids promote Von Hippel— Lindau degradation and Hif1a stabilization. Proc Natl Acad Sci USA 2017;114(37):9948—53. DOI: 10.1073/pnas.1705338114. PMID: 28851829.

78. Liu Z.J., Semenza G.L., Zhang H.F. Hypoxia-inducible factor 1 and breast cancer metastasis. J Zhejiang Univ Sci B 2015;16(1):32—43. DOI: 10.1631/jzus. B1400221. PMID: 25559953.

79. Лушникова А.А., Морозова Л.Ф., Абрамов И.С. и др. Генетические изменения в линии Рпоч1-КК cветлоклеточного рака почки человека. Успехи молекулярной онкологии 3(3):81—5. DOI: 10.17650/2313-805X-2016-3-3-81—85.

80. Park K., Lee H.E., Lee S.H. et al Molecular and functional evaluation of a novel HIF inhibitor, benzopyranyl 1,2,3-triazole compound. Oncotarget 2017;8(5): 7801—13. DOI: 10.18632/oncotarget.13955. PMID: 27999195.

81. Wang L.H., Jiang X.R., Yang J.Y. et al. SYP-5, a novel HIF1 inhibitor, suppresses tumor cells invasion and angiogenesis. Eur J Pharmacol 2016;791:560—8. DOI: 10.1016/j.ejphar.2016.09.027. PMID: 27664769.