Roles of pH in control of cell proliferation

Precise spatiotemporal regulation of intracellular pH ( pH i ) is a prerequisite for normal cell function, and changes in pH i or pericellular pH ( pH e ) exert important signalling functions. It is well established that proliferation of mammalian cells is dependent on a permissive pH i in the slightly alkaline range (7.0‐7.2). It is also clear that mitogen signalling in nominal absence of HCO 3 − is associated with an intracellular alkalinization (~0.3  pH unit above steady‐state pH i ), which is secondary to activation of Na + /H + exchange. However, it remains controversial whether this increase in pH i is part of the mitogenic signal cascade leading to cell cycle entry and progression, and whether it is relevant under physiological conditions. Furthermore, essentially all studies of pH i in mammalian cell proliferation have focused on the mitogen‐induced G0‐G1 transition, and the regulation and roles of pH i during the cell cycle remain poorly understood. The aim of this review is to summarize and critically discuss the possible roles of pH i and pH e in cell cycle progression. While the focus is on the mammalian cell cycle, important insights from studies in lower eukaryotes are also discussed. We summarize current evidence of links between cell cycle progression and pH i and discuss possible pH i ‐ and pH e sensors and signalling pathways relevant to mammalian proliferation control. The possibility that changes in pH i during cell cycle progression may be an integral part of the checkpoint control machinery is explored. Finally, we discuss the relevance of links between pH and proliferation in the context of the perturbed pH homoeostasis and acidic microenvironment of solid tumours.