Induction of a negative autocrine loop by expression of sst2 somatostatin receptor in NIH 3T3 cells.

Rauly, Isabelle; Saint-Laurent, Nathalie; Delesque, Nathalie; Buscail, Louis; Estève, Jean-Pierre; Vaysse, Nicole; Susini, Christiane

doi:10.1172/jci118618

Cited by 48 publications

(33 citation statements)

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“…This clone has been previously characterized. 11 As previously observed in NIH3T3/sst2 cells, sst2 expression in NIH3T3/sst2.1 cells increased DEVDase activity when compared with NIH3T3/mock cells (1.870.3-fold of NIH3T3/ mock cells; Figure 2a). These results indicated that the increase of DEVDase activity observed in sst2-expressing cells is indeed sst2-mediated and specific to sst2 expression.…”

Section: Resultssupporting

confidence: 83%

“…We previously demonstrated in NIH3T3 cells stably transfected with the human sst2 cDNA (NIH3T3/sst2), that the autocrine sst2-somatostatin loop results in cell growth inhibition. 11 We therefore investigated whether sst2 induces cell death in this previously described and characterized model. 11,12 We quantified apoptosis by using the terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique.…”

Section: Resultsmentioning

confidence: 99%

“…11 We therefore investigated whether sst2 induces cell death in this previously described and characterized model. 11,12 We quantified apoptosis by using the terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling (TUNEL) technique. After 5-h cell serum starvation, apoptosis in sst2-expressing cells was 3.6-71.2-fold higher than in mock cells (5.670.8 versus 1.570.5% of apoptotic cells, respectively) ( Figure 1a).…”

Section: Resultsmentioning

confidence: 99%

“…We previously reported that the tyrosine phosphatase SHP-1 is a critical sst2-signaling molecule in several models including NIH3T3 cells. 11,16,17 Therefore, we explored the implication of SHP-1 in sst2- sst2 stimulates NF-jB and sensitizes NIH3T3 cells to a TNFa-induced NF-jB activation. The transcription factor nuclear factor-kappa B (NF-kB) is a known regulator of apoptosis acting as a proapoptotic or antiapoptotic factor depending on the cell context.…”

Section: Resultsmentioning

confidence: 99%

“…11 sst2 antiproliferative action was evident in the absence of any addition of exogenous somatostatin and occurred as a consequence of an autocrine sst2-dependent loop whereby sst2 induces the expression of its own ligand, somatostatin. 11 We aimed to explore mechanisms for sst2 proapoptotic action using this cell model, and we therefore investigated whether sst2 expression induces cell death in NIH3T3 cells. We were also interested to investigate whether sst2 expression sensitizes NIH3T3 cells to apoptosis induced by the death ligand tumor necrosis factor a (TNFa).…”

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confidence: 99%

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Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways

et al. 2006

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Somatostatin is a multifunctional hormone that modulates cell proliferation, differentiation and apoptosis. Mechanisms for somatostatin-induced apoptosis are at present mostly unsolved. Therefore, we investigated whether somatostatin receptor subtype 2 (sst2) induces apoptosis in the nontransformed murine fibroblastic NIH3T3 cells. Somatostatin receptor subtype 2 expression induced an executioner caspase-mediated apoptosis through a tyrosine phosphatase SHP-1 (Src homology domain phosphatase-1)-dependent stimulation of nuclear factor kappa B (NF-jB) activity and subsequent inhibition of the mitogenactivated protein kinase JNK. Tumor necrosis factor a (TNFa) stimulated both NF-jB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFa-induced apoptosis by (1) upregulating TNFa receptor protein expression, and sensitizing to TNFa-induced caspase-8 activation; (2) enhancing TNFamediated activation of NF-jB, resulting in JNK inhibition and subsequent executioner caspase activation and cell death. We have here unraveled a novel signaling mechanism for a G protein-coupled receptor, which directly triggers apoptosis and crosstalks with a death receptor to enhance death ligand-induced apoptosis. Somatostatin is a regulatory peptide which is mostly expressed in the central and peripheral nervous system, in the gastro-intestinal tract and in the pancreas. Somatostatin acts via a family of five G protein-coupled receptors (GPCR), somatostatin receptor subtypes 1-5 (sst1-sst5) that are variably expressed throughout numerous tissues ranging from the central nervous system to the endocrine and immune systems. 1 Somatostatin or its analogues promote growth inhibition of various normal and tumor cells, both in vitro and in vivo. Somatostatin affects cell growth indirectly by inhibiting either trophic or growth factor synthesis and/or secretion, or their respective intracellular pathways. Somatostatin antiproliferative action also results from a direct blockade of cell cycle and/or induction of apoptosis. 2 Whereas somatostatin effect on cell cycle arrest has been extensively studied, mechanisms for somatostatin-induced apoptosis and receptor subtype implication are only partially elucidated. Somatostatin has been shown to induce cell death in both normal and tumoral cell models 3-9 . Among the five somatostatin receptors, sst3 and sst2 have been found to play a critical role in somatostatin-induced apoptosis of normal and tumor cells, respectively. 3,5,10 Mechanisms for somatostatin apoptotic action were shown to rely on the mitochondrial pathway through activation either of sst2 or sst3. However, signaling pathways coupling sst2 receptor to apoptosis have been partially elucidated.We have previously demonstrated that expression of sst2 in the nontransformated murine fibroblastic NIH3T3 cells results in a cell growth inhibition, which was dependent on the activation of the tyrosine phosphatase Src homology domain phosphatase-1 (SHP-1). 11 sst2...

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Section: Resultssupporting

confidence: 83%