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Humez S, Monet M, van Coppenolle F, Delcourt P, Prevarskaya N: The role of intracellular pH in cell growth arrest induced by ATP. Am J Physiol Cell Physiol. 2004 Dec;287(6):C1733-46. Epub 2004 Sep 8.
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 Ca (2+) influx, lowering extracellular Ca (2+), and buffering cytoplasmic Ca (2+) inhibited ATP-induced acidification, thereby demonstrating that acidification is a consequence of Ca (2+) entry. We show that ATP induced reuptake of Ca (2+) 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 Ca (2+) uptake into the mitochondria by ruthenium red, and after inhibition of the F (0) F (1)-ATPase with oligomycin. ATP-induced acidification was not induced by either stimulation of the Cl (-)/HCO (3)(-) exchanger or inhibition of the Na (+)/H (+) exchanger. In addition, intracellular acidification, induced by an ammonium prepulse method, reduced the amount of releasable Ca (2+) from the endoplasmic reticulum, assessed by measuring change in cytosolic Ca (2+) induced by thapsigargin or ATP in a Ca (2+)-free medium. This latter finding reveals cross talk between pH (i) and Ca (2+) homeostasis in which the Ca (2+)-induced intracellular acidification can in turn regulate the amount of Ca (2+) 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. |
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