МЕХАНИЗМЫ ПРОТОНИРОВАНИЯ МЕЖКЛЕТОЧНОГО ПРОСТРАНСТВА В ОПУХОЛЯХ

Одним из функциональных различий между нормальными и опухолевыми тканями является то, что в опухолях межклеточное пространство представляет собой более кислую среду по сравнению с внутриклеточной средой. Низкое значение рН во внеклеточном пространстве стимулирует инвазию и метастазирование по не совсем еще понятному механизму. Существует несколько путей поддержания низкого значения рН в опухолевом межклеточном пространстве. В процессе роста часть клеток опухоли находится в состоянии гипоксии. Считается, что инвазия и метастазирование происходят из гипоксических участков опухоли. При гипоксии благодаря функционированию транскрипционного фактора HIF-1α опухолевые клетки переходят на гликолиз, в результате чего конечным этапом окисления глюкозы является молочная кислота. Образование молочной кислоты из пирувата катализируется специфической HIF-1α-зависимой изоформой лактатдегидрогеназы. Накопление молочной кислоты с рК 3,9 опасно для клетки, и поэтому активизируются монокарбоксилат-транспортеры, выводящие из клетки лактат вместе с протоном, что вызывает подкисление межклеточного пространства. Другой механизм протонирования межклеточного пространства обусловлен функционированием опухоль-специфической HIF-1α-зависимой карбоновой ангидразы (СА IX), катализирующей образование протона при взаимодействии двуокиси углерода с водой. СА IX расположена в мембране клетки таким образом, что ее активный центр «повернут» в межклеточное пространство. Функционирование другой трансмембранной протонной помпы не связано с гипоксией. Активация Na+/H+-обменника происходит при стрессах типа осмотического шока и при действии пролиферативного стимула. В обзоре рассматриваются пути активации протонных помп; приводятся данные по действию различных типов ингибиторов их функционирования на рост клеток опухоли в культуре и in vivo; делается заключение о перспективности использования ингибиторов протонных помп в сочетании с «классическими» противоопухолевыми препаратами для лечения злокачественных новообразований.

инвазия и метастазирование, лактатдегидрогеназа, монокарбоксилат-транспортер, карбоновая ангидраза, Na+/H+-обменник, гипоксия, гликолиз, HIF-1α

1. Porporato P.E., Dhup S., Dadhich R.K. et al. Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review. Front Pharmacol 2011;25(2):1–18.

2. Koukourakis M.I., Giatromanolaki A., Simopoulos C. et al. Lactate dehydrogenase 5 (LDH5) relates to up-regulated hypoxia inducible factor pathway and metastasis in colorectal cancer. Clin Exp Metastasis 2005;22(1):25–30.

3. Koukourakis M.I., Giatromanolaki A., Sivridis E. et al. Lactate dehydrogenase-5 (LDH-5) overexpression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis. Br J Cancer 2003;89(5):877–85.

4. Leiblich A., Cross S.S., Catto J.W. et al. Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer. Oncogene 2006;25(20):2953–60.

5. Maciolek J.A., Pasternak J.A., Wilson H.L. Metabolism of activated T lymphocytes. Curr Opin Immunol 2014;27:60–74.

6. Frauwirth K.A., Thompson C.B. Regulation of T lymphocyte metabolism. J Immunol 2004;172(8):4661–5.

7. Fischer K., Hoffmann P., Voelkl S. et al. Inhibitory effect of tumor cell-derived lactic acid on human T cells. Blood 2007;109(9):3812–9.

8. 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.

9. Pinheiro C., Longatto-Filho A., Azevedo-Silva J. et al. Role of mono- carboxylate transporters in human cancers: state of the art. J Bioenerg Biomembr 2012;44(1):127–39.

10. Gao W., Zhang H., Chang G. et al. Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation. Cell Physiol Biochem 2014;33(1):185–94.

11. Estrella V., Chen T., Lloyd M. et al. Acidity generated by the tumor microenvironment drives local invasion. Cancer Res 2013;73(5):1524–35.

12. 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.

13. Halestrap A.P., Meredith D. The SLC16 gene family-from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch 2004;447(5):619–28.

14. Gatenby R.A., Smallbone K., Maini P.K. et al. Cellular adaptations to hypoxia and acidosis during somatic evolution of breast cancer. Br J Cancer 2007;97(5):646–53. 15. Brown J.M., Wilson W.R. Exploiting tumour hypoxia in cancer treatment. Nat Rev Cancer 2004;4(6):437–47.

15. Hoogsteen I.J., Marres H.A., Wijffels K.I. et al. Colocalization of carbonic anhydrase 9 expression and cell proliferation in human head and neck squamous cell carcinoma. Clin Cancer Res 2005;11(1):97–106.

16. Rauch C. Toward a mechanical control of drug delivery. On the relationship between Lipinski,s 2nd rule and cytosolic pH changes in doxorubicin resistance levels in cancer cells: a comparison to published data. Eur Biophys J 2009;38(7):829–46.

17. Raghunand N., He X., van Sluis R. et al. Enhancement of chemotherapy by manipulation of tumour pH. Br J Cancer 1999;80(7):1005–11.

18. Rofstad E.K., Mathiesen B., Kindem K. et al. Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice. Cancer Res 2006;66(13):6699–707.

19. Colen C.B., Shen Y., Ghoddoussi F. et al. Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study. Neoplasia 2011;13(7):620–32.

20. Ullah M.S., Davies A.J., Halestrap A.P. The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alpha-dependent mechanism. J Biol Chem 2006;281(14):9030–7.

21. Chiche J., Fur Y.L., Vilmen C. et al. In vivo pH in metabolic-defective Ras-transformed fibroblast tumors: key role of the monocarboxylate transporter, MCT4, for inducing an alkaline intracellular pH. Int J Cancer 2012;130(7):1511–20.

22. Draoui N., Feron O. Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments. Dis Model Mech 2011;4(6):727–32.

23. Kirk P., Wilson M.C., Heddle C. et al. CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression. EMBO J 2000;19(15):3896–904.

24. Wilson M.C., Meredith D., Fox J.E. et al. Basigin (CD147) is the target for organomercurial inhibition of monocarboxylate transporter isoforms 1 and 4, the ancillary protein for the insensitive MCT2 is EMBIGIN (gp70). J Biol Chem 2005;280(29):27213–21.

25. Nabeshima K., Iwasaki H., Koga K. et al. Emmprin (basigin/CD147): matrix metalloproteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression. Pathol Int 2006;56(7):359–67.

26. Dimmer K.S., Friedrich B., Lang F. et al. The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells. Biochem J 2000;350(Pt 1):219–27.

27. Sonveaux P., Vegran F., Schroeder T. et al. Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice. J Clin Invest 2008;118(12):3930–42.

28. Baltazar F., Pinheiro C., Morais-Santos F. et al. Monocarboxylate transporters as targets and mediators in cancer therapy response. Histol Histopathol 2014;29(12):1511–24.

29. Pértega-Gomes N., Baltazar F. Lactate transporters in the context of prostate cancer metabolism: what do we know? Int J Mol Sci 2014;15(10):18333–48.

30. Conde V., Oliveira P.F., Nunes A.R. et al. The progression from a lower to a higher invasive stage of bladder cancer is associated with severe alterations in glucose and pyruvate metabolism. Exp Cell Res 2015;335(1):91–8.

31. Pertega-Gomes N., Felisbino S., Massie C.E. et al. A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy. J Pathol 2015;236(4):517–30.

32. Choi J.W., Kim Y., Lee J.H., Kim Y.S. Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder. Urology 2014;84(1):245. e9–15.

33. Pinheiro C., Longatto-Filho A., Scapulatempo C. et al. Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas. Virchows Arch 2008;452(2):139–46.

34. Pinheiro C., Longatto-Filho A., Ferreira L. et al. Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma. Int J Gynecol Pathol 2008;27(4):568–74.

35. Doyen J., Trastour C., Ettore F. et al. Expression of the hypoxia-inducible monocarboxylate transporter MCT4 is increased in triple negative breast cancer and correlates independently with clinical outcome. Biochem Biophys Res Commun 2014;451(1):54–61.

36. Koukourakis M.I., Giatromanolaki A., Bougioukas G., Sivridis E. Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor associated stroma. Cancer Biol Ther 2007;6(9):1476–9.

37. Pinheiro C., Reis R.M., Ricardo S. et al. Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44. J Biomed Biotechnol 2010;2010:427694.

38. Morais-Santos F., Granja S., Miranda-Gonçalves V. et al. Targeting lactate transport suppresses in vivo breast tumour growth. Oncotarget 2015;6(22):19177–89.

39. Morais-Santos F., Miranda-Gonçalves V., Pinheiro S. et al. Differential sensitivities to lactate transport inhibitors of breast cancer cell lines. Endocr Relat Cancer 2013;21(1):27–38.

40. Mathupala S.P., Parajuli P., Sloan A.E. Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study. Neurosurgery 2004;55(6):1410–9.

41. Le Floch R., Chiche J., Marchiq I. et al. CD147 subunit of lactate/H+ symporters MCT1 and hypoxia-inducible MCT4 is critical for energetics and growth of glycolytic tumors. Proc Natl Acad Sci USA 2011;108(40):16663–8.

42. Marchiq I., Le Floch R., Roux D. et al. Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin. Cancer Res 2015;75(1):171–80.

43. Polanski R., Hodgkinson C.L., Fusi A. et al. Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer. Clin Cancer Res 2014;20(4):926–37.

44. Bola B.M., Chadwick A.L., Michopoulos F. et al. Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport. Mol Cancer Ther 2014;13(12):2805–16.

45. Draoui N., Schicke O., Seront E. et al. Antitumor activity of 7-aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux. Mol Cancer Ther 2014;13(6):1410–8.

46. Mahon B.P., Pinard M.A., McKenna R. Targeting carbonic anhydrase IX activity and expression. Molecules 2015;20(2):2323–48.

47. Pastorekova S., Parkkila S., Parkkila A.K. et al. Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts. Gastroenterology 1997;112(2):398–408.

48. Liao S.Y., Lerman M.I., Stanbridge E.J. Expression of transmembrane carbonic anhydrases, CAIX and CAXII, in human development. BMC Dev Biol 2009;9:22.

49. Karhumaa P., Parkkila S., Tureci O. et al. Identification of carbonic anhydrase XII

50. as the membrane isozyme expressed in the normal human endometrial epithelium. Mol Hum Reprod 2000;6(1):68–74.

51. Hynninen P., Hamalainen J.M., Pastorekova S. et al. Transmembrane carbonic anhydrase isozymes IX and XII in the female mouse reproductive organs. Reprod Biol Endocrinol 2004;2:73.

52. Parkkila S., Parkkila A.K., Saarnio J. et al. Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors. J Histochem Cytochem 2000;48(12):1601–8.

53. Kivela A.J., Parkkila S., Saarnio J. et al. Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours. Histochem Cell Biol 2000;114(3):197–204.

54. Liao S.Y., Ivanov S., Ivanova A. et al. Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12(CAXII) in glaucoma. J Med Genet 2003;40(4):257–61.

55. Hilvo M., Baranauskiene L., Salzano A.M. et al. Biochemical characterization of CA IX, one of the most active carbonic anhydrase isozymes. J Biol Chem 2008;283(41):27799–809.

56. Xu K., Mao X., Mehta M. et al. Elucidation of how cancer cells avoid acidosis through comparative transcriptomic data analysis. PloS One 2013;8(8):e71177.

57. Gorbatenko A., Olesen C.W., Boedtkjer E., Pedersen S.F. Regulation and roles of bicarbonate transporters in cancer. Front Physiol 2014;5:130.

58. Lou Y., McDonald P.C., Oloumi A. et al. Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors. Cancer Res 2011;7(9):3364–76.

59. Pacchiano F., Carta F., McDonald P.C. et al. Ureidosubstituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis. J Med Chem 2011;54(6):1896–902.

60. Touisni N., Maresca A., McDonald P.C. et al. Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors. J Med Chem 2011;54(24):8271–7.

61. Dubois L., Peeters S., Lieuwes N.G. et al. Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation. Radiother Oncol 2011;99(3):424–31.

62. Baumgartner M., Patel H., Barber D.L. Na(+)/H(+) exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes Am J Physiol Cell Physiol 2004;287(4):844–50.

63. Meima M.E., Mackley J.R., Barber D.L. Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1. Curr Opin Nephrol Hypertens 2007;16(4):365–72.

64. Slepkov E.R., Rainey J.K., Sykes B.D., Fliegel L. Structural and functional analysis of the Na+/H+ exchanger. Biochem J 2007;401(3):623–33.

65. Boedtkjer E., Bunch L., Pedersen S.F. Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy. Curr Pharm Des 2012;18(10):1345–71.

66. Hoffmann E.K., Lambert I., Pedersen S.F. Physiology of cell volume regulation in vertebrates. Physiol Rev 2009;89(1):193–277.

67. Pedersen S.F. The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death. Pflugers Arch 2006;452(3):249–59.

68. Reshkin S.J., Bellizzi A., Caldeira S. et al. Na+/H+ exchanger-dependent intracellular alkalinization is an early event in malignant transformation and plays an essential role in the development of subsequent transformation-associated phenotypes. FASEB J 2000;14(14):2185–97.

69. Aravena C., Beltran A.R., Cornejo M. et al. Potential role of sodium-proton exchangers in the low concentration arsenic trioxide-increased intracellular pH and cell proliferation. PLoS One 2012;7:e51451.

70. Reshkin S.J., Greco M.R., Cardone R.A. Role of pHi, and proton transporters in oncogene-driven neoplastic transformation. Philos Trans R Soc Lond B Biol Sci 2014;369(1638):20130100.

71. Fujiwara Y., Higuchi K., Takashima T. et al. Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury. Am J Physiol Gastrointest Liver Physiol 2006;290(4):665–7.

72. Amith S.R., Fliegel L. Regulation of the Na/H exchanger (NHE1) in breast cancer metastasis. Cancer Res 2013;73(4):1259–64.

73. Chiang Y., Chou C.Y., Hsu K.F. et al. EGF upregulates Na+/H+ exchanger NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness. J Cell Physiol 2008;214(3):810–9.

74. Yang X., Wang D., Dong W. et al. Inhibition of Na+/H+ exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility. Cancer Lett 2010;295(2):198–204.

75. Guan B., Hoque A., Xu X. Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts. Front Biol (Beijing) 2014;9(1):75–81.

76. Matthews H., Ranson M., Kelso M.J. Anti-tumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? Int J Cancer 2011;129(9):2051–61.

77. Tatsuta M., Iishi H., Baba M. et al. Chemoprevention by amiloride against experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague-Dawley rats. Cancer Lett 1997;119(1):109–13.

78. Sparfel L., Huc L., Le Vee M. et al. Inhibition of carcinogen-bioactivating cytochrome P4501 isoforms by amiloride derivatives. Biochem Pharmacol 2004;67(9):1711–9.

79. Lyons J.C., Ross B.D., Song C.W. Enhancement of hyperthermia effect in vivo by amiloride and DIDS. Int J Radiat Oncol Biol Phys 1993;25(1):95–103.

80. Nagata H., Che X.F., Miyazawa K. et al. Rapid decrease of intracellular pH associated with inhibition of Na+/H+ exchanger precedes apoptotic events in the MNK45 and MNK74 gastric cancer cell lines treated with 2-aminophenoxazine-3-one. Oncol Rep 2011;25(2):341–6.

81. Nakachi T., Tabuchi T., Takasaki A. et al. Anticancer activity of phenoxazines produced by bovine erythrocytes on colon cancer cells. Oncol Rep 2010;23(6):1517–22.

82. Zheng C.L., Che X.F., Akiyama S. et al. 2-Aminophenoxazine-3-one induces cellular apoptosis by causing rapid intracellular acidification and generating reactive oxygen species in human lung adenocarcinoma cells. Int J Oncol 2010;36(3):641–50.

83. Alfarouk K.O., Daniel Verduzco D., Rauch C. et al. Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question. Oncoscience 2014;1(12):777–802.

84. Harguindey S., Arranz J.L., Wahl M.L. et al. Proton transport inhibitors as potentially selective anticancer drugs. Anticancer Res 2009;29(6):2127–36. 30-42