The role of intracellular pH in cell growth arrest induced by ATP

In this study, we investigated ionic mechanisms involved in growth arrest induced by extracellular ATP in androgen-independent prostate cancer cells. Extracellular ATP reversibly induced a rapid and sustained intracellular pH (pHi) decrease from 7.41 to 7.11. Inhibition of Ca2+ influx, lowering extracellular Ca2+, and buffering cytoplasmic Ca2+ inhibited ATP-induced acidification, thereby demonstrating that acidification is a consequence of Ca2+ entry. We show that ATP induced reuptake of Ca2+ by the mitochondria and a transient depolarization of the inner mitochondrial membrane. ATP-induced acidification was reduced after the dissipation of the mitochondrial proton gradient by rotenone and carbonyl cyanide p-trifluoromethoxyphenylhydrazone, after inhibition of Ca2+ uptake into the mitochondria by ruthenium red, and after inhibition of the F0F1-ATPase with oligomycin. ATP-induced acidification was not induced by either stimulation of the Cl−/HCO3− exchanger or inhibition of the Na+/H+ exchanger. In additi...