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MEMBRANE TRANSPORTERS, ION CHANNELS, AND PUMPS

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

¹Laboratoire de Physiologie Cellulaire, INSERM EMI 0228, Université des Sciences et Technologies de Lille, 59655 Villeneuve d'Ascq Cedex; and ²Université d'Artois, Faculté Jean Perrin, 62300 Lens, France

Submitted 23 December 2003 ; accepted in final form 23 August 2004

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 (pH_i) 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 addition, intracellular acidification, induced by an ammonium prepulse method, reduced the amount of releasable Ca²⁺ from the endoplasmic reticulum, assessed by measuring change in cytosolic Ca²⁺ induced by thapsigargin or ATP in a Ca²⁺-free medium. This latter finding reveals cross talk between pH_i and Ca²⁺ homeostasis in which the Ca²⁺-induced intracellular acidification can in turn regulate the amount of Ca²⁺ that can be released from the endoplasmic reticulum. Furthermore, pH_i decrease was capable of reducing cell growth. Taken together, our results suggest that ATP-induced acidification in DU-145 cells results from specific effect of mitochondrial function and is one of the major mechanisms leading to growth arrest induced by ATP.

prostate; cancer; acidification