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

Abstract

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-κB) activity and subsequent inhibition of the mitogen-activated protein kinase JNK. Tumor necrosis factor α (TNFα) stimulated both NF-κB and c-Jun NH2-terminal kinase (JNK) activities, which had opposite action on cell survival. Importantly, sst2 sensitized NIH3T3 cells to TNFα-induced apoptosis by (1) upregulating TNFα receptor protein expression, and sensitizing to TNFα-induced caspase-8 activation; (2) enhancing TNFα-mediated activation of NF-κB, 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.