Role of Intracellular pH in Mammalian Cell Proliferation

Cytoplasmic pH of mammalian cells is regulated by Na+/H+ exchange and HCO-3 transport. In most proliferating cells, these systems collaborate to maintain pH in within a window of values that are permissive for growth. The enzyme systems whose ionization states and activities are affected by pH in this range are not known, but can include glycolysis, protein synthesis and degradation, and the DNA synthetic machinery. Thus, proper regulation of pH is a necessary, but not sufficient, criterion for proliferative control. On the other hand, there is mounting evidence that pH (and/or ΔΨ) ‘crises’ might be important to carcinogenesis. At least two different stages of in vitro carcinogenesis appear to have distinct (e.g. one acidic, one alkaline) pH optima. Once these stages have been passed, and the new phenotype is expressed, cells exhibit a decreased sensitivity to pH changes. The stage with the alkaline pH optimum can be induced by transfection with a H+-ATPase. This results in cells with homogeneous secondary phenotypic characteristics, such as: increased glycolysis, pH, Ca2+, constitutive fos expression and PDGF-independent growth. Furthermore, expression of H+-ATPases on the cell surface is observed in a subset of naturally occurring tumor cells.