Role of V-ATPases in solid tumors: Importance of the subunit C (Review)

Abstract

Abstract. Acidity is one of the main characteristics of OSCC (oral squamous cell carcinoma) as a solid tumor. The VATPase is the primary regulator of the tumor microenvironment, by means of proton extrusion to the extracellular medium. The decrease in extracellular pH confers the cells a resistant, highly invasive and metastatic phenotype. However, the acid medium confers an optimum pH to the degradative enzymes (such as proteases and MMPs) for their proper functioning. The C subunit (ATP6V1C) of V1 intra-membrane domain of the V-ATPase, is primarily responsible for its enzymatic function, through the control of a reversible dissociation of V0 and V1 domains. In this review, we describe the importance of V-ATPases in the control of tumor microenvironment, the potential strategies as protein targeting to improve the effectiveness of drug treatment and the role of the C subunit as the primarily responsible of the enzymatic control. The inhibition of the V-ATPase activity through PPIs (proton inhibitors) seems to reduce the destructive and metastatic capacity in tumors, such as hepatocellular carcinoma. Nevertheless, none of these inhibitors was proven to be useful in OSCC; therefore, it is highly important to carry out further studies in order to develop specific inhibitors of the C subunit, to control the devastating effects of OSCC. IntroductionThe main characteristics of the solid tumors (such as oral cancer) are the acidity and hypoxia, phenomena that result from the progression of metastatic cancer (1), the sensitivity to chemotherapeutic agents (2) and proliferation (3). In fact, a mechanism of resistance to cytotoxic drugs is the alteration of the pH gradient between the extracellular environment and cell cytoplasm (4).The cytosolic pH seems to be strictly regulated by four mechanisms: the family of sodium-proton exchangers (NHE), the family of bicarbonate transporters (BCT), the family of monocarboxylate transporters (MCT) and the proton pumps (ATPase) (5,6) ( Fig. 1). The lactate production has been commonly seen as the first acidification mechanism of the microenvironment (7). The lactate accumulation results in the activation of the aerobic glycolytic metabolism (8) which increases the amount of cellular lactate that is transported outside the cell through the H + /lactate co-transporter (MCT) (9). The increase in aerobic glycolysis (8,10) provides to the tumor a metabolic environment characterized by low levels of serum, hypoxia and an acid extracellular pH. This microenvironment increases the invasive ability of the tumor and the expression of growth and angiogenic factors/receivers (11). All this is correlated to an increment of the intracellular pH, an aggravation of the initial development of the interstitial acid microenvironment and a reversed transmembrane pH gradient (11,12). This increase in the intracellular pH is concomitant with an increment of DNA synthesis (8,13,14), cell cycle progression (15-17), serum and substrate-independent growth (8) and the in vivo growth of the tumor (8,18) and ...

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