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.
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Abbreviations
- EMSA:
-
electrophoretic mobility shift assay
- GPCR:
-
G protein-coupled receptor
- IL-1:
-
interleukin-1
- IκB:
-
inhibitory factor-kappa B
- JNK:
-
c-Jun NH2-terminal kinase
- MTT:
-
3-[4,5-dimethylthiazol-2-yl]-2,5-diphenyl tetrazolium bromide
- NF-κB:
-
nuclear factor-kappa B
- PAF-R:
-
platelet-activating factor-receptor
- PARP:
-
poly(ADP ribose) polymerase
- SHP-1:
-
Src homology domain phosphatase-1
- sst1–5:
-
somatostatin receptor subtypes 1–5
- TNF:
-
tumor necrosis factor
- TNFR1:
-
tumor necrosis factor receptor 1
- TUNEL:
-
terminal deoxynucleotidyltransferase (TdT)-mediated dUTP-biotin nick end labeling
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Acknowledgements
We are grateful to C Nahmias (ICGM, Paris, France) for providing SHP-1 constructs. This work was supported by grants from the Association pour la Recherche contre le Cancer (3219), Ligue Régionale contre le Cancer (R04045BB et R04044BB) and EC contract QLG3-CT-1999-00908.
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Guillermet-Guibert, J., Saint-Laurent, N., Davenne, L. et al. Novel synergistic mechanism for sst2 somatostatin and TNFα receptors to induce apoptosis: crosstalk between NF-κB and JNK pathways. Cell Death Differ 14, 197–208 (2007). https://doi.org/10.1038/sj.cdd.4401939
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DOI: https://doi.org/10.1038/sj.cdd.4401939
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