Interdependent regulation of intracellular acidification and SHP-1 in apoptosis

Muthusamy Thangaraju, Kamal Sharma, Danni Liu, Shi Hsiang Shen, Coimbatore B. Srikant

Research output: Contribution to journalArticle

103 Scopus citations

Abstract

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.

Original languageEnglish (US)
Pages (from-to)1649-1654
Number of pages6
JournalCancer Research
Volume59
Issue number7
StatePublished - Apr 1 1999
Externally publishedYes

ASJC Scopus subject areas

  • Oncology
  • Cancer Research

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  • Cite this

    Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., & Srikant, C. B. (1999). Interdependent regulation of intracellular acidification and SHP-1 in apoptosis. Cancer Research, 59(7), 1649-1654.