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Interdependent Regulation of Intracellular Acidification and SHP-1 in Apoptosis¹

Fraser Laboratories, McGill University and Royal Victoria Hospital [M. T., K. S., D. L., C. B. S.], and Pharmaceutical Sector, Biotechnology Research Institute, National Research Council of Canada [S-H. S.], Montreal, Quebec, H3A 1A1 Canada

The G protein-coupled receptor agonist somatostatin (SST)-induces apoptosis in MCF-7 human breast cancer cells. This is associated with induction of wild-type p53, Bax, and an acidic endonuclease. We have shown recently that its cytotoxic signaling is mediated via membrane-associated SHP-1 and is dependent on decrease in intracellular pH (pH_i) to 6.5. Here we investigated the relationship between intracellular acidification and SHP-1 in cytotoxic signaling. Clamping of pH_i at 7.25 by the proton-ionophore nigericin abolished SST-signaled apoptosis without affecting its ability to regulate SHP-1, p53, and Bax. Apoptosis could be induced by nigericin clamping of pH_i to 6.5. Such acidification-induced apoptosis was not observed at pH_i <6.0 or >6.7. pH_i-dependent apoptosis was associated with the translocation of SHP-1 to the membrane, enhanced in cells overexpressing SHP-1, and was abolished by its inactive mutant SHP-1C455S. Acidification caused by inhibition of Na⁺/H⁺ exchanger and H⁺ ATPase (pH_i = 6.55 and 6.65, respectively) also triggered apoptosis. The effect of concurrent inhibition of Na⁺/H⁺ exchanger and H⁺-ATPase on pH_i and apoptosis was comparable with that of SST. Acidification-induced, SHP-1-dependent apoptosis occurred in breast cancer cell lines in which SST was cytotoxic (MCF-7 and T47D) or not (MDA-MB-231). We conclude that: (a) SST-induced SHP-1-dependent acidification occurs subsequent to or independent of the induction of p53 and Bax; (b) SST-induced intracellular acidification may arise due to inhibition of Na⁺/H⁺ exchanger and H⁺-ATPase; and (c) SHP-1 is necessary not only for agonist-induced acidification but also for the execution of acidification-dependent apoptosis. We suggest that combined targeting of SHP-1 and intracellular acidification may lead to a novel strategy of anticancer therapy bypassing the need for receptor-mediated signaling.

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