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Успехи молекулярной онкологии

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МЕХАНИЗМЫ ПРОТОНИРОВАНИЯ МЕЖКЛЕТОЧНОГО ПРОСТРАНСТВА В ОПУХОЛЯХ

https://doi.org/10.17650/2313-805X.2015.2.3.21-29

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Аннотация

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.

Об авторе

В. А. Кобляков
Научно-исследовательский институт канцерогенеза ФГБУ «Российский онкологический научный центр имени Н.Н. Блохина» Минздрава России, Москва
Россия
Кобляков Валерий Александрович


Список литературы

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


Для цитирования:


Кобляков В.А. МЕХАНИЗМЫ ПРОТОНИРОВАНИЯ МЕЖКЛЕТОЧНОГО ПРОСТРАНСТВА В ОПУХОЛЯХ. Успехи молекулярной онкологии. 2015;2(3):21-29. https://doi.org/10.17650/2313-805X.2015.2.3.21-29

For citation:


Koblyakov V.A. THE MECHANISMS OF PROTONATION OF EXTRACELLULAR MATRIX IN TUMORS. Advances in molecular oncology. 2015;2(3):21-29. (In Russ.) https://doi.org/10.17650/2313-805X.2015.2.3.21-29

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