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 HCO3- 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.