Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P61278 (somatostatin)
 22,083 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Somatostatin (SST) analogs exert direct antiproliferative actions in pancreatic, pituitary, and mammary tumor cells in vitro. SST receptor (SSTR)-mediated induction of membrane-associated protein tyrosine phosphatase (PTP) activity has been implicated in its anti-proliferative signaling by virtue of its ability to dephosphorylate and inactivate growth factor receptor kinases. Recently, a PTP-containing Src homology 2 domain, identified as PTP1C/SHPTP1/SHP/HCP, was found to be associated with SSTR in rat pancreatic acinar cell membranes. In the present study we investigated the antiproliferative action of the octapeptide SST analog SMS 201-995 (OCT) and its effect on PTP activity in MCF-7 human breast adenocarcinoma cells. We report here that OCT does not directly stimulate membrane-associated PTP activity, but induces translocation of intracellular PTP to the membrane in MCF-7 cells preincubated with the peptide in a time- and concentration-dependent manner. We demonstrate that this is due at least in part to OCT-induced recruitment of cytosolic PTP1C. OCT-induced recruitment of PTP1C to the cell surface as well as its ability to inhibit the growth of MCF-7 cells was G protein dependent and inhibited by orthovanadate. These findings suggest that translocation of cytosolic PTP1C by SST analogs to the cell surface is an early event in its antiproliferative signaling in tumor cells.
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PMID:Octapeptide somatostatin analog SMS 201-995 induces translocation of intracellular PTP1C to membranes in MCF-7 human breast adenocarcinoma cells. 875 75

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 (pHi) to 6.5. Here we investigated the relationship between intracellular acidification and SHP-1 in cytotoxic signaling. Clamping of pHi 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 pHi to 6.5. Such acidification-induced apoptosis was not observed at pHi <6.0 or >6.7. pHi-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 (pHi = 6.55 and 6.65, respectively) also triggered apoptosis. The effect of concurrent inhibition of Na+/H+ exchanger and H(+)-ATPase on pHi 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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PMID:Interdependent regulation of intracellular acidification and SHP-1 in apoptosis. 1019 42

Recruitment of the SH2 domain containing cytoplasmic protein-tyrosine phosphatase SHP-1 to the membrane by somatostatin (SST) is an early event in its antiproliferative signaling that induces intracellular acidification-dependent apoptosis in breast cancer cells. Fas ligation also induces acidification-dependent apoptosis in a manner requiring the presence of SHP-1 at the membrane. Moreover, we have recently reported that SHP-1 is required not only for acidification, but also for apoptotic events that follow acidification (Thangaraju, M., Sharma, K., Liu, D., Shen, S. H., and Srikant, C. B. (1999) Cancer Res. 59, 1649-1654). Here we show that ectopically expressed SHP-1 was predominantly membrane-associated and amplified the cytotoxic signaling initiated upon SST receptor activation and Fas ligation. The catalytically inactive mutant of SHP-1 (SHP-1C455S) abolished the ability of the SST agonists to signal apoptosis by preventing the recruitment of wild type SHP-1 to the membrane. Overexpression of the anti-apoptotic protein Bcl-2 in MCF-7 cells inhibited SST-induced apoptosis upstream of acidification by inhibiting p53-dependent induction of Bax as well as by raising the resting pH(i) and attenuating SST-induced decrease in pH(i). By contrast, Bcl-2 failed to prevent apoptosis triggered by direct acidification. These data demonstrate that (i) membrane-associated SHP-1 is required for receptor-mediated cytotoxic signaling that causes intracellular acidification and apoptosis, and (ii) Bcl-2 acts distal to SHP-1 and p53 to prevent SST-induced acidification but cannot inhibit the apoptotic events that ensue intracellular acidification.
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PMID:Regulation of acidification and apoptosis by SHP-1 and Bcl-2. 1050 21