Biochemistry (Moscow)

, Volume 82, Issue 4, pp 401–412 | Cite as

Role of proton pumps in tumorigenesis

  • V. A. KobliakovEmail author


One of the differences between normal and cancer cells is lower pH of the extracellular space in tumors. Low pH in the extracellular space activates proteases and stimulates tumor invasion and metastasis. Tumor cells display higher level of the HIF1α transcription factor that promotes cell switch from mitochondrial respiration to glycolysis. The terminal product of glycolysis is lactate. Lactate formation from pyruvate is catalyzed by the specific HIF1α-dependent isoform of lactate dehydrogenase A. Because lactate accumulation is deleterious for the cell, it is actively exported by monocarboxylate transporters. Lactate is cotransported with proton, which acidifies the extracellular space. Another protein that contributes to proton concentration increase in the extracellular space is tumor-specific HIF1α-dependent carbonic anhydrase IX, which generates a proton in the reaction between carbon dioxide and water. The activity of Na+/H+ exchanger (another protein pump) is stimulated by stress factors (e.g. osmotic shock) and proliferation stimuli. This review describes the mechanisms of proton pump activation and reviews results of studies on effects of various proton pump inhibitors on tumor functioning and growth in cell culture and in vivo. The prospects of combined application of proton pump inhibitors and cytostatics in cancer therapy are discussed.


invasion metastasis lactate dehydrogenase monocarboxylate transporters carbonic anhydrase Na+/H+ exchanger hypoxia HIF1α 


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. 1.
    Lee, K. A., Roth, R. A., and LaPres, J. J. (2007) Hypoxia, drug therapy and toxicity, Pharmacol. Ther., 13, 229–463.CrossRefGoogle Scholar
  2. 2.
    Rankin, E. B., and Giaccia, A. J. (2016) Hypoxic control of metastasis, Science, 352, 175–180.PubMedPubMedCentralCrossRefGoogle Scholar
  3. 3.
    Lee, S. H., Lee, M. Y., and Han, H. J. (2008) Short-period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K/Akt signaling pathways, Cell Prolif., 41, 230–247.PubMedCrossRefGoogle Scholar
  4. 4.
    Zhao, T., Zhang, C. P., Liu, Z. H., Wu, L. Y., Huang, X., Wu, H. T., Xiong, L., Wang, X., Wang, X. M., Zhu, L. L., and Fan, M. (2008) Hypoxia-driven proliferation of embryonic neural stem/progenitor cells–role of hypoxia-inducible transcription factor-1alpha, FEBS J., 275, 1824–1834.PubMedCrossRefGoogle Scholar
  5. 5.
    Di Carlo, A., De Mori, R., Martelli, F., Pompilio, G., Capogrossi, M. C., and Germani, A. (2004) Hypoxia inhibits myogenic differentiation through accelerated MyoD degradation, J. Biol. Chem., 279, 16332–16338.PubMedCrossRefGoogle Scholar
  6. 6.
    Lin, Q., Lee, Y. J., and Yun, Z. (2006) Differentiation arrest by hypoxia, J. Biol. Chem., 281, 30678–30683.PubMedCrossRefGoogle Scholar
  7. 7.
    Krishnamachary, B., Berg-Dixon, S., Kelly, B., Agani, F., Feldser, D., Ferreira, G., Iyer, N., LaRusch, J., Pak, B., Taghavi, P., and Semenza, G. (2003) Regulation of colon carcinoma cell invasion by hypoxia-inducible factor 1, Cancer Res., 63, 1138–1143.PubMedGoogle Scholar
  8. 8.
    Robertson, S. E., Weaver, V. M., and Simon, M. C. (2005) Hypoxia-inducible factor regulates avß3 integrin cell surface expression, Mol. Biol. Cell, 16, 1901–1912.PubMedPubMedCentralCrossRefGoogle Scholar
  9. 9.
    Piret, J. P., Minet, E., Cosse, J. P., Ninane, N., Debacq, C., Raes, M., and Michiels, C. (2005) Hypoxia-inducible factor-1-dependent overexpression of myeloid cell factor-1 protects hypoxic cells against tert-butyl hydroperoxideinduced apoptosis, J. Biol. Chem., 280, 9336–9344.PubMedCrossRefGoogle Scholar
  10. 10.
    Brahimi-Horn, M. C., and Pouyssegur, J. (2007) Oxygen, a source of life and stress, FEBS Lett., 581, 3582–3591.PubMedCrossRefGoogle Scholar
  11. 11.
    Comerford, K. M., Wallace, T. J., Karhausen, J., Louis, N. A., Montalto, M. C., and Colgan, S. P. (2002) Hypoxiainducible factor-1-dependent regulation of the multidrug resistance (MDR1) gene, Cancer Res., 62, 3387–3394.PubMedGoogle Scholar
  12. 12.
    Li, D. W., Dong, P., Wang, F., Chen, X. W., Xu, C. Z., and Zhou, L. (2013) Hypoxia induced multidrug resistance of laryngeal cancer cells via hypoxia-inducible factor-1a, Asian Pac. J. Cancer Prev., 14, 4853–4858.PubMedCrossRefGoogle Scholar
  13. 13.
    Henegan, J. C., Jr., and Gomez, C. R. (2016) Heritable cancer syndromes related to the hypoxia pathway, Front. Oncol., doi: 10.3389/fonc.2016.00068.Google Scholar
  14. 14.
    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 HIFalpha prolyl hydroxylase, Cancer Cell, 7, 77–85.PubMedCrossRefGoogle Scholar
  15. 15.
    Nowicki, S., and Gottlieb, E. (2015) Oncometabolites: tailoring our genes, FEBS J., 282, 2796–2805.PubMedPubMedCentralCrossRefGoogle Scholar
  16. 16.
    Lai, F., Liu, Q., Liu, X., Ji, M., Xie, P., and Che, X. (2016) LXY6090–a novel manassantin A derivative–limits breast cancer growth through hypoxia-inducible factor-1 inhibition, Onco Targets Ther., 9, 3829–3840.PubMedPubMedCentralCrossRefGoogle Scholar
  17. 17.
    Tang, C. M., and Yu, J. (2013) Hypoxia-inducible factor-1 as a therapeutic target in cancer, J. Gastroenterol. Hepatol., 28, 401–405.PubMedCrossRefGoogle Scholar
  18. 18.
    Kolobova, E., Tuganova, A., Boulatnikov, I., and Popov, K. M. (2001) Regulation of pyruvate dehydrogenase activity through phosphorylation at multiple sites, Biochem. J., 358, 69–77.PubMedPubMedCentralCrossRefGoogle Scholar
  19. 19.
    Hitosugi, T., Fan, J., Chung, T. W., Lythgoe, K., Wang, X., Xie, J., Ge, Q., Gu, T. L., Polakiewicz, R. D., Roesel, J. L., Chen, G. Z., Boggon, T. J., Lonial, S., Fu, H., Khuri, F. R., Kang, S., and Chen, J. (2011) Tyrosine phosphorylation of mitochondrial pyruvate dehydrogenase kinase 1 is important for cancer metabolism, Mol. Cell, 44, 864–877.PubMedPubMedCentralCrossRefGoogle Scholar
  20. 20.
    Kim, J. W., Tchernyshyov, I., Semenza, G. L., and Dang, C. V. (2006) HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia, Cell. Metab., 3, 177–185.PubMedCrossRefGoogle Scholar
  21. 21.
    Wigfield, S. M., Winter, S. C., Giatromanolaki, A., Taylor, J., Koukourakis, M. L., and Harris, A. L. (2008) PDK-1 regulates lactate production in hypoxia and is associated with poor prognosis in head and neck squamous cancer, Br. J. Cancer, 98, 1975–1984.PubMedPubMedCentralCrossRefGoogle Scholar
  22. 22.
    Kroemer, G., and Pouyssegur, J. (2008) Tumor cell metabolism: cancer’s Achilles’ heel, Cancer Cell, 13, 472–482.PubMedCrossRefGoogle Scholar
  23. 23.
    Zhang, W., Zhang, S.-L., Hu, X., and Tam, K. Y. (2015) Targeting tumor metabolism for cancer treatment: is pyruvate dehydrogenase kinases (PDKs) a viable anticancer target? Int. J. Biol. Sci., 11, 1390–1400.PubMedPubMedCentralCrossRefGoogle Scholar
  24. 24.
    Lu, H., Forbes, R. A., and Verma, A. (2002) Hypoxiainducible factor 1 activation by aerobic glycolysis implicates the Warburg effect in carcinogenesis, J. Biol. Chem., 277, 23111–23115.PubMedCrossRefGoogle Scholar
  25. 25.
    Porporato, P. E., Dhup, S., Dadhich, R. K., Copetti, T., and Sonveaux, P. (2011) Anticancer targets in the glycolytic metabolism of tumors: a comprehensive review, Front. Pharmacol., 25, 1–18.Google Scholar
  26. 26.
    Valvona, C. J., Fillmore, H. L., Nunn, P. B., and Pilkington, G. J. (2016) The regulation and function of lactate dehydrogenase A: therapeutic potential in brain tumor, Brain Pathol., 26, 3–17.PubMedCrossRefGoogle Scholar
  27. 27.
    Lu, H., Dalgard, C. L., Mohyeldin, A., McFate, T., Tait, A. S., and Verma, A. (2005) Reversible inactivation of HIF-1 prolyl hydroxylases allows cell metabolism to control basal HIF-1, J. Biol. Chem., 280, 41928–41939.PubMedCrossRefGoogle Scholar
  28. 28.
    Koukourakis, M. I., Giatromanolaki, A., Simopoulos, C., Polychronidis, A., and Sivridis, E. (2005) Lactate dehydrogenase 5 (LDH5) relates to upregulated hypoxia inducible factor pathway and metastasis in colorectal cancer, Clin. Exp. Metastasis, 22, 25–30.PubMedCrossRefGoogle Scholar
  29. 29.
    Koukourakis, M. I., Giatromanolaki, A., and Sivridis, E. (2003) Lactate dehydrogenase-5 (LDH-5) over expression in non-small-cell lung cancer tissues is linked to tumour hypoxia, angiogenic factor production and poor prognosis, Br. J. Cancer, 89, 877–885.Google Scholar
  30. 30.
    Leiblich, A., Cross, S. S., Catto, J. W., Phillips, J. T., Leung, H. Y., Hamdy, F. C., and Rehman, I. (2006) Lactate dehydrogenase-B is silenced by promoter hypermethylation in human prostate cancer, Oncogene, 25, 2953–2960.PubMedCrossRefGoogle Scholar
  31. 31.
    Fantin, V. R., St-Pierre, J., and Leder, P. (2006) Attenuation of LDH-A expression uncovers a link between glycolysis, mitochondrial physiology, and tumor maintenance, Cancer Cell, 9, 425–434.PubMedCrossRefGoogle Scholar
  32. 32.
    Yao, F., Zhao, T., Zhong, C., Zhu, J., and Zhao, H. (2013) LDHA is necessary for the tumorigenicity of esophageal squamous cell carcinoma, Tumour Biol., 34, 25–31.PubMedCrossRefGoogle Scholar
  33. 33.
    Merkle, S., Favor, J., Graw, J., Hornhardt, S., and Pretsch, W. (1992) Hereditary lactate dehydrogenase A-subunit deficiency as cause of early postimplantation death of homozygotes in Mus musculus, Genetics, 131, 413–421.PubMedPubMedCentralGoogle Scholar
  34. 34.
    Gao, W., Zhang, H., Chang, G., Xie, Z., Wang, H., Ma, L., Han, Z., Li, Q., and Pang, T. (2014) Decreased intracellular pH induced by cariporide differentially contributes to human umbilical cord-derived mesenchymal stem cells differentiation, Cell. Physiol. Biochem., 33, 185–194.PubMedCrossRefGoogle Scholar
  35. 35.
    Maciolek, J. A., Pasternak, J. A., and Wilson, H. L. (2014) Metabolism of activated T lymphocytes, Curr. Opin. Immunol., 27, 7436–7438.CrossRefGoogle Scholar
  36. 36.
    Frauwirth, K. A., and Thompson, C. B. (2004) Regulation of T lymphocyte metabolism, J. Immunol., 172, 4661–4665.PubMedCrossRefGoogle Scholar
  37. 37.
    Fischer, K., Hoffmann, P., Voelkl, S., Meidenbauer, N., Ammer, J., Edinger, M., Gottfried, E., Schwarz, S., Rothe, G., Hoves, S., Renner, K., Timischl, B., Mackensen, A., Kunz-Schughart, L., Andreesen, R., Krause, S. W., and Kreutz, M. (2007) Inhibitory effect of tumor cell derived lactic acid on human T cells, Blood, 109, 3812–3819.PubMedCrossRefGoogle Scholar
  38. 38.
    Pinheiro, C., Longatto-Filho, A., Azevedo-Silva, J., Casal, M., Schmitt, F. C., and Baltazar, F. (2012) Role of monocarboxylate transporters in human cancers: state of the art, J. Bioenerg. Biomembr., 44, 127–139.PubMedCrossRefGoogle Scholar
  39. 39.
    Lambert, C. A., Colige, A. C., Mineur, P., Noël, A., Frankenne, F., Foidart, J. M., Baba, M., Hata, R., Miyazaki, K., and Tsukuda, M. (2005) Acidic extracellular pH induces matrix metalloproteinase-9 expression in mouse metastatic melanoma cells through the phospholipase D-mitogen-activated protein kinase signaling, J. Biol. Chem., 280, 10938–10944.PubMedCrossRefGoogle Scholar
  40. 40.
    Deryugina, E. L., and Quigley, J. P. (2012) Cell surface remodeling by plasmin: a new function for an old enzyme, J. Biomed. Biotechnol., Article ID564259.Google Scholar
  41. 41.
    Rofstad, E. K., Mathiesen, B., Kindem, K., and Galappathi, K. (2006) Acidic extracellular pH promotes experimental metastasis of human melanoma cells in athymic nude mice, Cancer Res., 66, 6699–6707.PubMedCrossRefGoogle Scholar
  42. 42.
    Ben-Haim, S., and Ell, P. (2009) 18F-FDG PET and PET/CT in the evaluation of cancer treatment response, J. Nucl. Med., 50, 88–99.PubMedCrossRefGoogle Scholar
  43. 43.
    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.PubMedPubMedCentralCrossRefGoogle Scholar
  44. 44.
    Brown, J. M., and Wilson, W. R. (2004) Exploiting tumor hypoxia in cancer treatment, Nat. Rev. Cancer, 4, 437–447.PubMedCrossRefGoogle Scholar
  45. 45.
    Masoud, G. N., and Li, W. (2015) HIF-1a pathway: role, tregulation and intervention for cancer therapy, cta Pharm. Sin. B5, 378–389.CrossRefGoogle Scholar
  46. 46.
    Rauch, C. (2009) 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., 38, 829–846.PubMedCrossRefGoogle Scholar
  47. 47.
    Raghunand, N., He, X., Van Sluis, R., Mahoney, B., Baggett, B., Taylor, C. W., Paine-Murrieta, G., Roe, D., Bhujwalla, Z. M., and Gillies, R. J. (1999) Enhancement of chemotherapy by manipulation of tumour pH, Br. J. Cancer, 80, 1005–1011.PubMedPubMedCentralCrossRefGoogle Scholar
  48. 48.
    Masoud, G. N., Wang, J., Chen, J., Miller, D., and Li, W. (2015) Design, synthesis and biological evaluation of novel HIF1a inhibitors, Anticancer Res., 35, 3849–3859.PubMedGoogle Scholar
  49. 49.
    Halestrap, A. P. (2012) The monocarboxylate transporter family–structure and functional characterization, IUBMB Life, 64, 1–9.PubMedCrossRefGoogle Scholar
  50. 50.
    Halestrap, A. P., and Meredith, D. (2004) C16 gene family–from monocarboxylate transporters (MCTs) to aromatic amino acid transporters and beyond, Pflug. Arch., 447, 619–628.CrossRefGoogle Scholar
  51. 51.
    Brahimi-Horn, M. C., Bellot, G., and Pouyssegur, J. (2011) Hypoxia and energetic tumour metabolism, Curr. Opin. Genet. Dev., 21, 67–72.PubMedCrossRefGoogle Scholar
  52. 52.
    Ullah, M. S., Davies, A. J., and Halestrap, A. P. (2006) The plasma membrane lactate transporter MCT4, but not MCT1, is up-regulated by hypoxia through a HIF-1alphadependent mechanism, J. Biol. Chem., 281, 9030–9037.PubMedCrossRefGoogle Scholar
  53. 53.
    Halestrap, A. P. (2013) The SLC16 gene family–structure, role and regulation in health and disease, Mol. Asp. Med., 34, 337–349.CrossRefGoogle Scholar
  54. 54.
    Draoui, N., and Feron, O. (2011) Lactate shuttles at a glance: from physiological paradigms to anti-cancer treatments, Dis. Model. Mech., 4, 727–732.PubMedPubMedCentralCrossRefGoogle Scholar
  55. 55.
    Kirk, P., Wilson, M. C., Heddle, C., Brown, M. H., Barclay, A. N., and Halestrap, A. P. (2000) CD147 is tightly associated with lactate transporters MCT1 and MCT4 and facilitates their cell surface expression, EMBO J., 19, 3896–3904.PubMedPubMedCentralCrossRefGoogle Scholar
  56. 56.
    Wilson, M. C., Meredith, D., Fox, J. E., Manoharan, C., Davies, A. J., and Halestrap, A. P. (2005) 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., 280, 27213–27221.PubMedCrossRefGoogle Scholar
  57. 57.
    Nabeshima, K., Iwasaki, H., Koga, K., Hojo, H., Suzumiya, J., and Kikuchi, M. (2006) Emmprin (basigin/CD147): matrix metallo-proteinase modulator and multifunctional cell recognition molecule that plays a critical role in cancer progression, Pathol. Int., 56, 359–367.PubMedCrossRefGoogle Scholar
  58. 58.
    Dimmer, K. S., Friedrich, B., Lang, F., Deitmer, J. W., and Broer, S. (2000) The low-affinity monocarboxylate transporter MCT4 is adapted to the export of lactate in highly glycolytic cells, Biochem. J., 350, 219–227.PubMedPubMedCentralCrossRefGoogle Scholar
  59. 59.
    Brooks, G. A. (2009) Cell–cell and intracellular lactate shuttles, J. Physiol., 587, 5591–5600.PubMedPubMedCentralCrossRefGoogle Scholar
  60. 60.
    Baltazar, F., Pinheiro, C., Morais-Santos, F., AzevedoSilva, J., Queiros, O., Preto, A., and Casal, M. (2014) Monocarboxylate transporters as targets and mediators in cancer therapy response, Histopathology, 29, 1511–1524.Google Scholar
  61. 61.
    Pertega-Gomes, N., and Baltazar, F. (2014) Lactate transporters in the context of prostate cancer metabolism: what do we know? Int. J. Mol. Sci., 15, 18333–18348.PubMedPubMedCentralCrossRefGoogle Scholar
  62. 62.
    Conde, V., Oliveira, P. F., Nunes, A. R., Rocha, C. S., Ramalhosa, E., Pereira, J. A., Alves, M. G., and Silva, B. M. (2015) 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., 335, 91–98.PubMedCrossRefGoogle Scholar
  63. 63.
    Pertega-Gomes, N., Felisbino, S., Massie, C. E., Vizcaino, J. R., Coelho, R., Sandi, C., Simoes-Sousa, S., Jurmeister, S., Ramos-Montoya, A., Asim, M., Tran, M., Oliveira, E., Lobo da Cunha, A., Maximo, V., Baltazar, F., Neal, D. E., and Fryer, L. G. (2015) A glycolytic phenotype is associated with prostate cancer progression and aggressiveness: a role for monocarboxylate transporters as metabolic targets for therapy, J. Pathol., 236, 517–530.PubMedPubMedCentralCrossRefGoogle Scholar
  64. 64.
    Choi, J. W., Kim, Y., Lee, J. H., and Kim, Y. S. (2014) Prognostic significance of lactate/proton symporters MCT1, MCT4, and their chaperone CD147 expressions in urothelial carcinoma of the bladder, Urology, 84, e9–e15.CrossRefGoogle Scholar
  65. 65.
    Pinheiro, C., Longatto-Filho, A., Scapulatempo, C., Ferreira, L., Martins, S., Pellerin, L., Rodrigues, M., Alves, V. A., Schmitt, F., and Baltazar, F. (2008) Increased expression of monocarboxylate transporters 1, 2, and 4 in colorectal carcinomas, Virch. Arch., 452, 139–146.CrossRefGoogle Scholar
  66. 66.
    Pinheiro, C., Longatto-Filho, A., Ferreira, L., Pereira, S. M., Etlinger, D., Moreira, M. A., Jube, L. F., Queiroz, G. S., Schmitt, F., and Baltazar, F. (2008) Increasing expression of monocarboxylate transporters 1 and 4 along progression to invasive cervical carcinoma, Int. J. Gynecol. Pathol., 27, 568–574.PubMedCrossRefGoogle Scholar
  67. 67.
    Doyen, J., Trastour, C., Ettore, F., Peyrottes, I., Toussant, N., Gal, J., Ilc, K., Roux, D., Parks, S. K., Ferrero, J. M., and Pouyssegur, J. (2014) 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., 451, 54–61.PubMedCrossRefGoogle Scholar
  68. 68.
    Koukourakis, M. I., Giatromanolaki, A., Bougioukas, G., and Sivridis, E. (2007) Lung cancer: a comparative study of metabolism related protein expression in cancer cells and tumor-associated stroma, Cancer Biol. Ther., 6, 1476–1479.PubMedCrossRefGoogle Scholar
  69. 69.
    Pinheiro, C., Reis, R. M., Ricardo, S., Longatto-Filho, A., Schmitt, F., and Baltazar, F. (2010) Expression of monocarboxylate transporters 1, 2, and 4 in human tumours and their association with CD147 and CD44, J. Biomed. Biotechnol., 427694.Google Scholar
  70. 70.
    Morais-Santos, F., Granja, S., Miranda-Goncalve, V., Moreira, A. H., Queiros, S., Vilaca, J. L., Schmitt, F. C., Longatto-Filho, A., Paredes, J., Baltazar, F., and Pinheiro, C. (2015) Targeting lactate transport suppresses in vivo breast tumour growth, Oncotarget, 6, 9177–9189.CrossRefGoogle Scholar
  71. 71.
    Morais-Santos, F., Miranda-Goncalves, V., Pinheiro, S., Vieira, A. F., Paredes, J., Schmitt, F. C., Baltazar, F., and Pinheiro, C. (2013) Differential sensitivities to lactate transport inhibitors of breast cancer cell lines, Endocrin. Relat. Cancer, 21, 27–38.CrossRefGoogle Scholar
  72. 72.
    Mathupala, S. P., Parajuli, P., and Sloan, A. E. (2004) Silencing of monocarboxylate transporters via small interfering ribonucleic acid inhibits glycolysis and induces cell death in malignant glioma: an in vitro study, Neurosurgery, 55, 1410–1419.PubMedCrossRefGoogle Scholar
  73. 73.
    Colen, C. B., Shen, Y., Ghoddoussi, F., Yu, P., Francis, T. B., Koch, B. J., Monterey, M. D., Galloway, M. P., Sloan, A. E., and Mathupala, S. P. (2011) Metabolic targeting of lactate efflux by malignant glioma inhibits invasiveness and induces necrosis: an in vivo study, Neoplasia, 13, 620–632.PubMedPubMedCentralCrossRefGoogle Scholar
  74. 74.
    Sonveaux, P., Vegran, F., Schroeder, T., Wergin, M. C., Verrax, J., Rabbani, Z. N., De Saedeleer, C. J., Kennedy, K. M., Diepart, C., Jordan, B. F., Kelley, M. J., Gallez, B., Wahl, M. L., Feron, O., and Dewhirst, M. W. (2008) Targeting lactate-fueled respiration selectively kills hypoxic tumor cells in mice, J. Clin. Invest., 118, 3930–3942.PubMedPubMedCentralGoogle Scholar
  75. 75.
    Le Floch, R., Chiche, J., Marchiq, I., Naiken, T., Ilc, K., Murray, C. M., Critchlow, S. E., Roux, D., Simon, M. P., and Pouyssegur, J. (2011) 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, 108, 16663–16668.PubMedPubMedCentralCrossRefGoogle Scholar
  76. 76.
    Marchiq, I., Le Floch, R., Roux, D., Simon, M. P., and Pouyssegur, J. (2015) Genetic disruption of lactate/H+ symporters (MCTs) and their subunit CD147/BASIGIN sensitizes glycolytic tumor cells to phenformin, Cancer Res., 75, 171–180.PubMedCrossRefGoogle Scholar
  77. 77.
    Polanski, R., Hodgkinson, C. L., Fusi, A., Nonaka, D., Priest, L., Kelly, P., Trapani, F., Bishop, P. W., White, A., Critchlow, S. E., Smith, P. D., Blackhall, F., Dive, C., and Morrow, C. J. (2014) Activity of the monocarboxylate transporter 1 inhibitor AZD3965 in small cell lung cancer, Clin. Cancer Res., 20, 926–937.PubMedCrossRefGoogle Scholar
  78. 78.
    Bola, B. M., Chadwick, A. L., Michopoulos, F., Blount, K. G., Telfer, B. A., Williams, K. J., Smith, P. D., Critchlow, S. E., and Stratford, I. J. (2014) Inhibition of monocarboxylate transporter-1 (MCT1) by AZD3965 enhances radiosensitivity by reducing lactate transport, Mol. Cancer Ther., 13, 2805–2816.PubMedPubMedCentralCrossRefGoogle Scholar
  79. 79.
    A phase I trial of AZD3965 in patients with advanced cancer;; Identifier: NCT01791595.Google Scholar
  80. 80.
    Draoui, N., Schicke, O., Seront, E., Bouzin, C., Sonveaux, P., Riant, O., and Feron, O. (2014) Antitumor activity of 7aminocarboxycoumarin derivatives, a new class of potent inhibitors of lactate influx but not efflux, Mol. Cancer Ther., 13, 1410–1418.PubMedCrossRefGoogle Scholar
  81. 81.
    Mahon, B. P., Pinard, M. A., and McKenna, R. (2015) Targeting carbonic anhydrase IX activity and expression, Molecules, 20, 2323–2348.PubMedCrossRefGoogle Scholar
  82. 82.
    Pastorekova, S., Parkkila, S., Parkkila, A. K., Opavsky, R., Zelnik, V., Saarnio, J., and Pastorek, J. (1997) Carbonic anhydrase IX, MN/CA IX: analysis of stomach complementary DNA sequence and expression in human and rat alimentary tracts, Gastroenterology, 112, 398–408.PubMedCrossRefGoogle Scholar
  83. 83.
    Liao, S. Y., Lerman, M. I., and Stanbridge, E. J. (2009) Expression of transmembrane carbonic anhydrases, CAIX and CAXII, in human development, BMC Dev Biol., 9, 22.PubMedPubMedCentralCrossRefGoogle Scholar
  84. 84.
    Karhumaa, P., Parkkila, S., Tureci, O., Waheed, A., Grubb, J. H., Shah, G., Parkkila, A., Kaunisto, K., Tapanainen, J., Sly, W. S., and Rajaniemi, H. (2000) Identification of carbonic anhydrase XII as the membrane isozyme expressed in the normal human endometrial epithelium, Mol. Hum. Reprod., 6, 68–74.PubMedCrossRefGoogle Scholar
  85. 85.
    Hynninen, P., Hamalainen, J. M., Pastorekova, S., Pastorek, J., Waheed, A., Sly, W. S., Tomas, E., Kirkinen, P., and Parkkila, S. (2004) Transmembrane carbonic anhydrase isozymes IX and XII in the female mouse reproductive organs, Reprod. Biol. Endocrinol., 2, 73.PubMedPubMedCentralCrossRefGoogle Scholar
  86. 86.
    Parkkila, S., Parkkila, A. K., Saarnio, J., Kivela, J., Karttunen, T. J., Kaunisto, K., Waheed, A., Sly, W. S., Tureci, O., Virtanen, I., and Rajaniemi, H. (2000) Expression of the membrane-associated carbonic anhydrase isozyme XII in the human kidney and renal tumors, J. Histochem. Cytochem., 48, 1601–1608.PubMedCrossRefGoogle Scholar
  87. 87.
    Kivela, A. J., Parkkila, S., Saarnio, J., Karttunen, T. J., Kivela, J., Parkkila, A. K., Pastorekova, S., Pastorek, J., Waheed, A., Sly, W. S., and Rajaniemi, H. (2000) Expression of transmembrane carbonic anhydrase isoenzymes IX and XII in normal human pancreas and pancreatic tumours, Histochem. Cell. Biol., 114, 197–204.PubMedGoogle Scholar
  88. 88.
    Liao, S. Y., Ivanov, S., Ivanova, A., Ghosh, S., Cote, M. A., Keefe, K., Coca-Prados, M., Stanbridge, E. J., and Lerman, M. I. (2003) Expression of cell surface transmembrane carbonic anhydrase genes CA9 and CA12 in the human eye: overexpression of CA12 (CAXII) in glaucoma, J. Med. Genet., 40, 257–261.PubMedPubMedCentralCrossRefGoogle Scholar
  89. 89.
    Hilvo, M., Baranauskiene, L., Salzano, A. M., Scaloni, A., Matulis, D., Innocenti, A., Scozzafava, A., Monti, S. M., Di Fiore, A., De Simone, G., Lindfors, M., Janis, J., Valjakka, J., Pastorekova, S., Pastorek, J., Kulomaa, M. S., Nordlund, H. R., Supuran, C. T., and Parkkila, S. (2008) Biochemical characterization of CAIX, one of the most active carbonic anhydrase isozymes, J. Biol. Chem., 283, 27799–27809.PubMedCrossRefGoogle Scholar
  90. 90.
    Gorbatenko, C. W., Olesen, E., Boedtkjer, S., and Pedersen, F. (2014) Regulation and roles of bicarbonate transporters in cancer, Front. Physiol., 5, doi: 10.3389/fphys.2014.00130.Google Scholar
  91. 91.
    Lou, Y., McDonald, P. C., Oloumi, A., Chia, S., Ostlund, C., Ahmadi, A., Kyle, A., Leung, S., Huntsman, D., Clarke, B., Sutherland, B. W., Waterhouse, D., Bally, M., Roskelley, C., Overall, C. M., Minchinton, A., Pacchiano, F., Carta, F., Scozzafava, A., Touisni, N., Winum, J. Y., Supuran, C. T., and Dedhar, S. (2011) Targeting tumor hypoxia: suppression of breast tumor growth and metastasis by novel carbonic anhydrase IX inhibitors, Cancer Res., 71, 3364–3376.PubMedCrossRefGoogle Scholar
  92. 92.
    Pacchiano, F., Carta, F., McDonald, P. C., Lou, Y., Vullo, D., Scozzafava, A., Dedhar, S., and Supuran, C. T. (2011) Ureidosubstituted benzenesulfonamides potently inhibit carbonic anhydrase IX and show antimetastatic activity in a model of breast cancer metastasis, J. Med. Chem., 54, 1896–1902.PubMedCrossRefGoogle Scholar
  93. 93.
    Touisni, N., Maresca, A., McDonald, P. C., Lou, Y., Scozzafava, A., Dedhar, S., Winum, J. Y., and Supuran, C. T. (2011) Glycosyl coumarin carbonic anhydrase IX and XII inhibitors strongly attenuate the growth of primary breast tumors, J. Med. Chem., 54, 8271–8277.PubMedCrossRefGoogle Scholar
  94. 94.
    Dubois, L., Peeters, S., Lieuwes, N. G., Geusens, N., Thiry, A., Wigfield, S., Carta, F., McIntyre, A., Scozzafava, A., Dogne, J. M., Supuran, C. T., Harris, A. L., Masereel, B., and Lambin, P. (2011) Specific inhibition of carbonic anhydrase IX activity enhances the in vivo therapeutic effect of tumor irradiation, J. Eur. Soc. Ther. Radiol. Oncol., 99, 424–431.CrossRefGoogle Scholar
  95. 95.
    Dubois, L. J., Niemans, R., Van Kuijk, S. J., Panth, K. M., Parvathaneni, N. K., Peeters, S. G., Zegers, C. M., Rekers, N. H., Van Gisbergen, M. W., Biemans, R., Lieuwes, N. G., Spiegelberg, L., Yaromina, A., Winum, J. Y., Vooijs, M., and Lambin, P. (2015) New ways to image and target tumour hypoxia and its molecular responses, Radiother. Oncol., 116, 352–357.PubMedCrossRefGoogle Scholar
  96. 96.
    Baumgartner, M., Patel, H., and Barber, D. L. (2004) Na+/H+ exchanger NHE1 as plasma membrane scaffold in the assembly of signaling complexes, Am. J. Physiol. Cell. Physiol., 287, C844–850.PubMedCrossRefGoogle Scholar
  97. 97.
    Meima, M. E., Mackley, J. R., and Barber, D. L. (2007) Beyond ion translocation: structural functions of the sodium-hydrogen exchanger isoform-1, Curr. Opin. Nephrol. Hypertens., 16, 365–372.PubMedCrossRefGoogle Scholar
  98. 98.
    Slepkov, E. R., Rainey, J. K., Sykes, B. D., and Fliegel, L. (2007) Structural and functional analysis of the Na+/H+ exchanger, Biochem. J., 401, 623–633.PubMedPubMedCentralCrossRefGoogle Scholar
  99. 99.
    Boedtkjer, E., Bunch, L., and Pedersen, S. F. (2012) Physiology, pharmacology and pathophysiology of the pH regulatory transport proteins NHE1 and NBCn1: similarities, differences, and implications for cancer therapy, Curr. Pharmaceut. Des., 18, 1345–1371.CrossRefGoogle Scholar
  100. 100.
    Hoffmann, E. K., Lambert, I., and Pedersen, S. F. (2009) Physiology of cell volume regulation in vertebrates, Physiol. Rev., 89, 193–277.PubMedCrossRefGoogle Scholar
  101. 101.
    Pedersen, S. F. (2006) The Na+/H+ exchanger NHE1 in stress-induced signal transduction: implications for cell proliferation and cell death, Pflugers’ Arch. Eur. J. Physiol., 452, 249–259.CrossRefGoogle Scholar
  102. 102.
    Reshkin, S. J., Bellizzi, A., Caldeira, S., Albarani, V., Malanchi, I., Poignee, M., Alunni-Fabbroni, M., Casavola, V., and Tommasino, M. (2000) 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., 14, 2185–2197.PubMedCrossRefGoogle Scholar
  103. 103.
    Aravena, C., Beltran, A. R., Cornejo, M., Torres, V., Diaz, E. S., Guzman-Gutierrez, E., Pardo, F., Leiva, A., Sobrevia, L., and Ramirez, M. A. (2012) Potential role of sodium-proton exchangers in the low concentration arsenic trioxide-increased intracellular pH and cell proliferation, PLoS One, 7, e51451.PubMedPubMedCentralCrossRefGoogle Scholar
  104. 104.
    Reshkin, S. J., Greco, M. R., and Cardone, R. A. (2014) Role of pHi, and proton transporters in oncogene-driven neoplastic transformation, Phil. Trans. R. Soc. Lond. Ser. B Biol. Sci., 369, 20130100.CrossRefGoogle Scholar
  105. 105.
    Reshkin, S. J., Cardone, R. A., and Harguindey, S. (2013) Na+-H+ exchanger, pH regulation and cancer, Rec. Pat. Anti Cancer Drug Discov., 8, 85–99.CrossRefGoogle Scholar
  106. 106.
    Reshkin, S. J., Cardone, R. A., Zeeberg, K., Greco, M. R., and Harguindey, S. (2014) The Na+-H+ exchanger (NHE1) in pH regulation and cancer, Top. Anti Cancer Res., 3, 384–417.Google Scholar
  107. 107.
    Stylli, S. S., Kaye, A. H., and Lock, P. (2008) Invadopodia: at the cutting edge of tumour invasion, J. Clin. Neurosci., 15, 725–737.PubMedCrossRefGoogle Scholar
  108. 108.
    Yamaguchi, H. (2012) Pathological roles of invadopodia in cancer invasion and metastasis, Eur. J. Cell. Biol., 91, 902–907.PubMedCrossRefGoogle Scholar
  109. 109.
    Greco, M. R., Antelmi, E., Busco, G., Guerra, L., Rubino, R., Casavola, V., Reshkin, S. J., and Cardone, R. A. (2014) Protease activity at invadopodial focal digestive areas is dependent on NHE1-driven acidic pHe, Oncol. Rep., 31, 940–946.PubMedGoogle Scholar
  110. 110.
    Busco, G., Cardone, R. A., Greco, M. R., Bellizzi, A., Colella, M., Antelmi, E., Mancini, M. T., Dell’Aquila, M. E., Casavola, V., Paradiso, A., and Reshkin, S. J. (2010) NHE1 promotes invadopodial ECM proteolysis through acidification of the peri-invadopodial space, FASEB J., 24, 3903–3915.PubMedCrossRefGoogle Scholar
  111. 111.
    Fujiwara, Y., Higuchi, K., Takashima, T., Hamaguchi, M., Hayakawa, T., Tominaga, K., Watanabe, T., Oshitani, N., Shimada, Y., and Arakawa, T. (2006) Roles of epidermal growth factor and Na+/H+ exchanger-1 in esophageal epithelial defense against acid-induced injury, Am. J. Physiol. Gastrointest. Liver Physiol., 290, G665–667.PubMedCrossRefGoogle Scholar
  112. 112.
    Amith, S. R., and Fliegel, L. (2013) Regulation of the Na/H exchanger (NHE1) in breast cancer metastasis, Cancer Res., 73, 1259–1264.PubMedCrossRefGoogle Scholar
  113. 113.
    Chiang, Y., Chou, C. Y., Hsu, K. F., Huang, Y. F., and Shen, M. R. (2008) EGF upregulates Na+/H+ exchanger NHE1 by post-translational regulation that is important for cervical cancer cell invasiveness, J. Cell. Physiol., 214, 810–819.PubMedCrossRefGoogle Scholar
  114. 114.
    Yang, X., Wang, D., and Dong, W. (2010) Inhibition of Na+/H+ exchanger 1 by 5-(N-ethyl-N-isopropyl) amiloride reduces hypoxia-induced hepatocellular carcinoma invasion and motility, Cancer Lett., 295, 198–204.PubMedCrossRefGoogle Scholar
  115. 115.
    Guan, B., Hoque, A., and Xu, X. (2014) Amiloride and guggulsterone suppression of esophageal cancer cell growth in vitro and in nude mouse xenografts, Front. Biol. (Beijing), 9, 75–81.CrossRefGoogle Scholar
  116. 116.
    Matthews, H., Ranson, M., and Kelso, M. J. (2011) Antitumour/metastasis effects of the potassium-sparing diuretic amiloride: an orally active anti-cancer drug waiting for its call-of-duty? Int. J. Cancer, 129, 2051–2061.PubMedCrossRefGoogle Scholar
  117. 117.
    Tatsuta, M., Iishi, H., and Baba, M. (1997) Chemoprevention by amiloride against experimental hepatocarcinogenesis induced by N-nitrosomorpholine in Sprague–Dawley rats, Cancer Lett., 119, 109–113.PubMedCrossRefGoogle Scholar
  118. 118.
    Sparfel, L., Huc, L., Le Vee, M., Desille, M., LagadicGossmann, D., and Fardel, O. (2004) Inhibition of carcinogen-bioactivating cytochrome P450 1 isoforms by amiloride derivatives, Biochem. Pharmacol., 67, 1711–1719.PubMedCrossRefGoogle Scholar
  119. 119.
    Lyons, J. C., Ross, B. D., and Song, C. W. (1993) Enhancement of hyperthermia effect in vivo by amiloride and DIDS, Int. J. Radiat. Oncol. Biol. Phys., 25, 103.CrossRefGoogle Scholar
  120. 120.
    Nagata, H., Che, X. F., Miyazawa, K., Tomoda, A., Konishi, M., Ubukata, H., and Tabuchi, T. (2011) 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., 25, 341–346.PubMedGoogle Scholar
  121. 121.
    Nakachi, T., Tabuchi, T., Takasaki, A., Arai, S., Miyazawa, K., and Tomoda, A. (2010) Anticancer activity of phenoxazines produced by bovine erythrocytes on colon cancer cells, Oncol. Rep., 23, 1517–1522.PubMedGoogle Scholar
  122. 122.
    Zheng, C. L., Che, X. F., Akiyama, S., Miyazawa, K., and Tomoda, A. (2010) 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., 36, 641–650.PubMedGoogle Scholar
  123. 123.
    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, Transl. Med., 11, 282 doi: 10.1186/1479–5876–11–282.CrossRefGoogle Scholar
  124. 124.
    Alfarouk, K. O., Verduzco, D., Rauch, C., Muddathir, A. K., Bashir, A. H., Elhassan, G. O., Ibrahim, M. E., Orozco, J. D., Cardone, R. A., Reshkin, S. J., and Harguindey, S. (2014) Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question, Oncoscience, 1, 777–802.PubMedPubMedCentralCrossRefGoogle Scholar
  125. 125.
    Osinsky, S., and Vaupel, M. (2009) Microphysiology of Tumors [in Russian], Naukova Dumka, Kiev.Google Scholar
  126. 126.
    McCarty, M. F., and Whitaker, J. (2010) Manipulating tumor acidification as a cancer treatment strategy, Altern. Med. Rev., 15, 264–272.PubMedGoogle Scholar
  127. 127.
    Trivedi, B., and Danforth, W. H. (1966) Effect of pH on the kinetics of frog muscle phosphofructokinase, J. Biol. Chem., 241, 4110–4112.PubMedGoogle Scholar
  128. 128.
    Guzy, R. D., and Schumacker, P. T. (2008) Oxygen sensing by mitochondria at complex III: the paradox of increased reactive oxygen species during hypoxia, Exp. Physiol., 91, 807–819.CrossRefGoogle Scholar
  129. 129.
    Giang, A. H., Raymond, T., Brookes, P., De Mesy Bentley, K., Schwarz, E., O’ Keefe, R., and Eliseev, R. (2013) Mitochondrial dysfunction and permeability transition in osteosarcoma cells showing the Warburg effect, J. Biol. Chem., 288, 33303–33311.PubMedPubMedCentralCrossRefGoogle Scholar
  130. 130.
    Gasparre, G., Romeo, G., Rugolo, M., and Porcelli, A. M. (2011) Learning from oncocytic tumors: why choose inefficient mitochondria? Biochim. Biophys. Acta, 1807, 633–642.PubMedCrossRefGoogle Scholar
  131. 131.
    Cordero-Espinoza, L., and Hagen, T. (2013) Increased concentrations of fructose 2,6-bisphosphate contribute to the Warburg effect in phosphatase and tensin homolog (PTEN)-deficient cells, J. Biol. Chem., 288, 36020–36028.PubMedPubMedCentralCrossRefGoogle Scholar
  132. 132.
    Harguindey, S., Arranz, J. L., Wahl, M. L., Orive, G., and Reshkin, S. J. (2009) Proton transport inhibitors as potentially selective anticancer drugs, Anticancer Res., 29, 2127–2136.PubMedGoogle Scholar

Copyright information

© Pleiades Publishing, Ltd. 2017

Authors and Affiliations

  1. 1.Blokhin Russian Cancer Research CenterRussian Ministry of HealthMoscowRussia

Personalised recommendations