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S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer.

ABSTRACT: One of the key features of tumor cells is the acquisition of resistance to apoptosis. Thus, novel therapeutic strategies that circumvent apoptotic resistance and result in tumor elimination are needed. One strategy to induce apoptosis is to activate death receptor signaling pathways. In the tumor microenvironment, stimulation of Fas, Death receptor 4 (DR4) and tumor necrosis factor receptor 1 (TNFR1) can initiate multiple signaling pathways driving either tumor promotion or elimination. Nitric oxide (NO) is an important signaling molecule now understood to play a dual role in cancer biology. More and more attention is directed toward the role displayed by S-nitrosylation, the incorporation of an NO moiety to a cysteine thiol group, in promoting cell death in tumor cells. Protein post-translation modification by S-nitrosylation has decisive roles in regulating signal-transduction pathways. In this review, we summarize several examples of protein modification by S-nitrosylation that regulate signaling pathways engaged by members of the TNF superfamily (Fas ligand (FasL), Tumor-necrosis-factor-related apoptosis inducing ligand (TRAIL) and TNFalpha (TNF?)) and the way it influences cell fate decisions.

SUBMITTER: Plenchette S

PROVIDER: S-EPMC4600855 | biostudies-literature | 2015 Dec

REPOSITORIES: biostudies-literature

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S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer.

Plenchette Stéphanie S Romagny Sabrina S Laurens Véronique V Bettaieb Ali A

Redox biology 20150908

One of the key features of tumor cells is the acquisition of resistance to apoptosis. Thus, novel therapeutic strategies that circumvent apoptotic resistance and result in tumor elimination are needed. One strategy to induce apoptosis is to activate death receptor signaling pathways. In the tumor microenvironment, stimulation of Fas, Death receptor 4 (DR4) and tumor necrosis factor receptor 1 (TNFR1) can initiate multiple signaling pathways driving either tumor promotion or elimination. Nitric o ...[more]

PMID: 26448396

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Project description:S-nitrosylation and S-glutathionylation, redox-based modifications of protein thiols, are recently emerging as important signaling mechanisms. In this study, we assessed S-nitrosylation-based regulation of Janus-activated kinase 2/signal transducer and activator of transcription 3 (JAK2/STAT3) pathway that plays critical roles in immune/inflammatory responses and tumorigenesis.Our studies show that STAT3 in stimulated microglia underwent two distinct redox-dependent modifications, S-nitrosylation and S-glutathionylation. STAT3 S-nitrosylation was associated with inducible nitric oxide synthase (iNOS)-produced nitric oxide (NO) and S-nitrosoglutathione (GSNO), whereas S-glutathionylation of STAT3 was associated with cellular oxidative stress. NO produced by iNOS or treatment of microglia with exogenous GSNO inhibited STAT3 activation via inhibiting STAT3 phosphorylation (Tyr(705)). Consequently, the interleukin-6 (IL-6)-induced microglial proliferation and associated gene expressions were also reduced. In cell-free kinase assay using purified JAK2 and STAT3, STAT3 phosphorylation was inhibited by its selective preincubation with GSNO, but not by preincubation of JAK2 with GSNO, indicating that GSNO-mediated mechanisms inhibit STAT3 phosphorylation through S-nitrosylation of STAT3 rather than JAK2. In this study, we identified that Cys(259) was the target Cys residue of GSNO-mediated S-nitrosylation of STAT3. The replacement of Cys(259) residue with Ala abolished the inhibitory role of GSNO in IL-6-induced STAT3 phosphorylation and transactivation, suggesting the role of Cys(259) S-nitrosylation in STAT3 phosphorylation.Microglial proliferation is regulated by NO via S-nitrosylation of STAT3 (Cys(259)) and inhibition of STAT3 (Tyr(705)) phosphorylation.Our results indicate the regulation of STAT3 by NO-based post-translational modification (S-nitrosylation). These findings have important implications for the development of new therapeutics targeting STAT3 for treating diseases associated with inflammatory/immune responses and abnormal cell proliferation, including cancer.

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S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer.

Publications

S-Nitrosylation in TNF superfamily signaling pathway: Implication in cancer.

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