Abstract
The review presents and discusses data on the role of changes in pH outside and inside of a cell that are caused by aerobic glycolysis in tumor tissue. In comparison with normal tissue in a tumor, there is acidification of the intercellular space and an increase in pH inside the tumor cells. The main factor in the regulation of glycolysis is the HIF α transcription factor. The change in pH is due to the fact that the final product of glucose conversion is not pyruvate, but lactate. Lactate is transported across the cell membrane and acidifies the intercellular space. In addition, HIF α factor causes the transcription of a number of proton pumps and matrix proteinases, which are activated in the acidic environment of the intercellular space. The intercellular matrix is destroyed, which allows tumor cells to invade. The acidification of the intercellular space due to the functioning of proton pumps causes an increase in the pH inside the cells. An increase in intracellular pH stimulates the accelerated passage of cells through the phase G2 cell cycle. The molecular mechanisms of this process are discussed. It is concluded that the main factors of the tumor process—invasion, accelerated proliferation, and genome instability are due to aerobic glycolysis (the Warburg effect).
Similar content being viewed by others
REFERENCES
Aggarwa, N. and Sloane, B.F., Cathepsin B: multiple roles in cancer, Proteomics Clin. Appl., 2014, vol. 8, p. 427. https://doi.org/10.1002/prca.201300105
Alfarouk, K.O., Verduzco, D., Rauch, C., Mudda-thir, A.K., Adil, H.H.B., Elhassan, G.O., Ibrahim, M.E., Orozco, J.D.P., Cardone, R., Reshkin, S.J., and Harguindey, S., Glycolysis, tumor metabolism, cancer growth and dissemination. A new pH-based etiopathogenic perspective and therapeutic approach to an old cancer question, Oncoscience, 2014, vol. 1, p. 777.
Alfarouk, K.O., Ahmed, S.B.M., Elliott, R.L., Benoit, A., Alqahtan, S.S., Ibrahim, M.E., Bashir, A.H., Alhoufie, S.T.S., Elhassan, G.O., Wales, C.C., and Reshkin, S.J., The pentose phosphate pathway dynamics in cancer and its dependency on intracellular pH, Metabolites, 2020, vol. 10, p. 285. https://doi.org/10.3390/metabo10070285
Bazylianska V., Kalpage H.A., Wan J., Vaishnav A., Mahapatra G., Turner A.A., D.D., Kim K., Morse P.T., Lee I., Brunzelle J.S. Lysine 53 acetylation of cytochrome c in prostate cancer: Warburg metabolism and evasion of apoptosis. Cells, 2021, vol. 10, p. 802. https://doi.org/10.3390/cells10040802 Beck, H., Nähse, V., Larsen, M.S., Groth, P., Clancy, T., Lees, M., Jørgensen, M., Helleday, T., Syljuåsen, R.G., Sørensen, C.S. Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase. J. Cell. Biol. , 2010, vol. 188, p. 629.
Benizri, B.E., Ginouve, E., Volmat, V., Roux, D., PouysBeck, H., Nähse, V., Larsen, M.S., Groth, P., Clancy, T., Lees, M., Jørgensen, M., Helleday, T., Syljuåsen, R.G., and Sørensen, C.S., Regulators of cyclin-dependent kinases are crucial for maintaining genome integrity in S phase, J. Cell. Biol., 2010, vol. 188, p. 629.
Birkeland, E.S., Koch, L.M., and Dechant, R., Another consequence of the Warburg effect? Metabolic regulation of Na+/H+ exchangers may link aerobic glycolysis to cell growth, Front. Oncol., 2020, vol. 10, p. 1561. https://doi.org/10.3389/fonc.2020.01561
Cash, T.P., Pan, Y., and Simon, M.C., Reactive oxygen species and cellular oxygen sensing, Free Radical Biol. Med., 2007, vol. 43, p. 1219.
Chandel, N.S., McClintock, D.S., Feliciano, C.E., Wood, T.M., Melendez, J.A., Rodriguez, A.M., and Schumacker, P.T., Reactive oxygen species generated at mitochondrial complex III stabilize hypoxia-inducible factor-1alpha during hypoxia: a mechanism of O2 sensing, J. Biol. Chem., 2000, vol. 275, p. 25130.
Xiaofei, C., Yanqing, L., Dongkai, Z., Dong, C., Feng, Z., and Weilin, W., Identification of cathepsin B as a novel target of hypoxia-inducible factor-1-alpha in HepG2 cells, Biochem. Biophys. Res. Commun., 2018, vol. 503, p. 1057. https://doi.org/10.1016/j.bbrc.2018.06.116
Choueiri, T.K., and Kaelin, W.G., Jr., Targeting the HIF2-VEGF axis in renal cell carcinoma, Nat. Med., 2020, vol. 26, p. 1519. https://doi.org/10.1038/s41591-020-1093-z
Czowski, B.J., Romero-Moreno, R., Trull, K.J., and White, K.A., Cancer and pH dynamics: transcriptional regulation, proteostasis, and the need for new molecular tools, Cancers, 2020, vol. 12, p. 2760. https://doi.org/10.3390/cancers12102760
Deryugina, E.L. and Quigley, J.P., Cell surface remodeling by plasmin: a new function for an old enzyme, J. Biomed. Biotechnol., 2012, vol. 2012, article ID 564259. https://doi.org/10.1155/2012/564259
Druker, J., Wilson, J.W., Child, F., Shakir, D., Fasanya, T., and Rocha, S., Role of hypoxia in the control of the cell cycle, Int. J. Mol. Sci., 2021, vol. 22, p. 4874. https://doi.org/10.3390/ijms22094874
Estrella, V., Chen, T., and Lloyd, M., Acidity generated by the tumor microenvironment drives local invasion, Cancer Res., 2013, vol. 73, p. 1524.
Fais, S., Venturi, G., and Gatenby, B., Microenvironmental acidosis in carcinogenesis and metastases: new strategies in prevention and therapy, Cancer Metastasis Rev., 2014, vol. 33, p. 1095.
Gao, X., Zhang, Y., Zhang, R., Zhao, Z., Zhang, H., Wu, J., Shen, W., and Zhong, M., Cyclin-dependent kinase 1 disruption inhibits angiogenesis by inducing cell cycle arrest and apoptosis, Exp. Ther. Med., 2019, vol. 18, p. 3062. https://doi.org/10.3892/etm.27883
Ghelli A di Rorà, L., Cerchione, C., Martinelli, G., and Simonetti, G., A WEE1 family business: regulation of mitosis, cancer progression, and therapeutic target, J. Hematol. Oncol., 2020, vol. 13, article 126. https://doi.org/10.1186/s13045-020-00959-2
Harguindey, S., Arranz, J.L., Polo Orozco, J.D., Rauch, C., Fais, S., Cardone, R.A., and Reshkin, S.J., 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, vol. 11, p. 282. https://doi.org/10.1186/1479-5876-11-282
Hubbi, M.E., Gilkesa, D.M., Hu, H., Ahmede, I., and Semenza, G.L., Cyclin-dependent kinases regulate lysosomal degradation of hypoxia-inducible factor 1α to promote cell-cycle progression, Proc. Natl. Acad. Sci. U. S. A., 2014, vol. 111, article ID E3325.
Jing, S.-W., Wang, Y.-D., Kuroda, M., Su, J.-W., Sun, G.-G., Liu, Q., Cheng, Y.-J., and Yang, C.-R., HIF-1α contributes to hypoxia-induced invasion and metastasis of esophageal carcinoma via inhibiting E-cadherin and promoting MMP-2 expression, Acta Med. Okayama, 2012, vol. 66, p. 399. https://doi.org/10.18926/AMO/48964
Kato, Y., Lambert, C.A., Colige, A.C., Mineur, P., Noël, A., Frankenne, F., Foidart, J.M., Baba, M., Hata, R., Miyazaki, K., and Tsukuda, M., 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., 2005, vol. 25, p. 10938.
Kim, J.W., Tchernyshyov, I., Semenza, G.L., and Dang, C.V., HIF-1-mediated expression of pyruvate dehydrogenase kinase: a metabolic switch required for cellular adaptation to hypoxia, Cell Metab., 2006, vol. 3, p. 177.
Kobliakov, V.A., Mechanisms of tumor promotion by reactive oxygen species, Biochemistry (Moscow), 2010, vol. 75, no. 6, p. 757.
Kobliakov, V.A., Role of proton pumps in tumorigenesis, Biochemistry (Moscow), 2017, vol. 82, no. 4, p. 401.
Kobliakov, V.A., The mechanisms of regulation of aerobic glycolysis (Warburg effect) by oncoproteins in carcinogenesis, Biochemistry (Moscow), 2019, vol. 84, no. 10, p. 1117. https://doi.org/10.1134/S0006297919100018
Lee, K.A., Roth, R.A., and LaPres, J.J., Hypoxia, drug therapy and toxicity, Pharmacol. Ther., 2007, vol. 13, p. 229.
Lee, S.H., Lee, M.Y., and Han, H.J., Short-period hypoxia increases mouse embryonic stem cell proliferation through cooperation of arachidonic acid and PI3K/Akt signalling pathways, Cell Prolif., 2008, vol. 41, p. 230.
Lee, G., Won, H.S., Lee, Y.M., Choi, J.W., Oh, T.I., Jang, J.H., Choi, D.K., Lim, B.O., Kim, Y.J., Park, J.W., Puigserver, P., and Lim, J.H., Oxidative dimerization of PHD2 is responsible for its inactivation and contributes to metabolic reprogramming via HIF-1α activation, Sci. Rep., 2016, vol. 6, p. 18928. https://doi.org/10.1038/srep18928
Lu, H., Forbes, R.A., and Verma, A., Hypoxia-inducible factor 1 activation by aerobic glycolysis implicates the warburg effect in carcinogenesis, J. Biol. Chem., 2002, vol. 277, p. 23111.
Ma, G., Li, C., Zhang, Z., Liang, Ye, Liang, Z., Chen, Y., Wang, L., Li, D., Zeng, M., and Niu, H., Targeted glucose or glutamine metabolic therapy combined with PD-1/PD-L1 checkpoint blockade immunotherapy for the treatment of tumors, mechanisms and strategies, Front. Oncol., 2021, vol.11, article 697894. https://doi.org/10.3389/fonc.2021.697894
Martin, N.K., Robey, I.F., and Gaffney, E.A., Predicting the safety and efficacy of buffer therapy to raise tumour pH: an integrative modelling study, Br. J. Cancer, 2012, vol. 106, p. 1280.
Masoud, G.N. and Li, W., HIF-1α pathway: role, regulation and intervention for cancer therapy, Acta Pharm. Sin. B, 2015, vol. 5, p. 378.
McCarty, M.F. and Whitaker, J., Manipulating tumor acidification as a cancer treatment strategy, Altern. Med. Rev., 2010, vol. 15, p. 264.
Ning Cui, Min Hu, and Raouf, A., Khalil biochemical and biological attributes of matrix metalloproteinases, Prog. Mol. Biol. Transl. Sci., 2017, vol. 147, p. 1. https://doi.org/10.1016/bs.pmbts.2017.02.005
Putney, D.L. and Barber, L.K., Na−H exchange-dependent increase in intracellular pH times G2/M entry and transition, J. Biol. Chem., 2003, vol. 278, p. 44645.https://doi.org/10.1074/jbc.M308099200
Putney, D.L. and Barber, LK., Expression profile of genes regulated by activity of the Na-H exchanger NHE1, BMC Genomics, 2004, vol. 16, p. 46. https://doi.org/10.1186/1471-2164-5-46
Reshkin, S.J., Bellizzi, A., Caldeira, S., Albarani, V., Malanchi, I., Poignee, M., Alunni-Fabbroni, M., Casavola, V., and Tommasino, M., 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, vol. 14, p. 2185.
Schmid, M., Rohe, A., Platzer, C., Najja, A., Erdmann, F., and Sippl, W., Regulation of G2/M transition by inhibition of WEE1 and PKMYT1 kinases, Molecules, 2017, vol. 22, p. 2045. https://doi.org/10.3390/molecules22122045
Schönichen, B., Webb, A., Jacobson, M.P., and Barbe, D.L., Considering protonation as a posttranslational modification regulating protein structure and function, Ann. Rev. Biophys., 2013, vol. 42, p. 289.
Sur, S. and Agrawa, D.K., Phosphatases and kinases regulating CDC25 activity in the cell cycle: clinical implications of Cdc25 overexpression and potential treatment strategies, Mol. Cell. Biochem., 2016, vol. 416, p. 33. https://doi.org/10.1007/s11010-016-2693-2
Warburg, O., Posener, K., and Negelein, E., Über den S-toffwechsel der Karzinomzellen, Biochemische Zeitschrift, 1924, vol. 152, p. 309.
Warfel, N.A., Dolloff, N.G., Dicker, D.T., Malysz, J., and, El-Deiry, W.S., CDK1 stabilizes HIF-1α via direct phosphorylation of Ser668 to promote tumor growth, Cell Cycle, 2013, vol. 12, p. 3689.
White, K.A., Grillo-Hil, B.K., and Baber, D.L., Cancer cell behaviors mediated by dysregulated pH dynamics at a glance, J. Cell. Sci., 2017, vol. 130, p. 663. https://doi.org/10.1242/jcs.195297
Williger, B.T., Ho, W.T., and Exton, J.H., Phospholipase D mediates matrix metalloproteinase-9 secretion in phorbol ester-stimulated human fibrosarcoma cells, J. Biol. Chem., 1999, vol. 274, p. 735. https://doi.org/10.1074/jbc.274.2.735
Zhang, H., Yang, Q., Lian, X., Jiang, P., and Cu, J., Hypoxia-inducible factor-1α (HIF-1α) promotes hypoxia-induced invasion and metastasis in ovarian cancer by targeting matrix metallopeptidase 13 (MMP13), Med. Sci. Monit., 2019, vol. 25, p. 7202.
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., Hypoxia-driven proliferation of embryonic neural stem/progenitor cells-role of hypoxia-inducible transcription factor-1alpha, FEBS J., 2008, vol. 275, p. 1824.
Funding
This work was carried out at the expense of budgetary funding of the Blokhin Scientific Research Medical Center of Oncology.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
The author declares that he has no conflicts of interest. No animals or human beings took part in the experiments.
Rights and permissions
About this article
Cite this article
Kobliakov, V.A. The Role of Extra- and Intracellular pH Values in Regulation of the Tumor Process. Cell Tiss. Biol. 16, 114–120 (2022). https://doi.org/10.1134/S1990519X22020079
Received:
Revised:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1134/S1990519X22020079