S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells. - Université de Rennes Accéder directement au contenu
Article Dans Une Revue Gastroenterology Année : 2011

S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells.

Résumé

BACKGROUND & AIMS: Fas belongs to the family of tumor necrosis factor receptors which induce apoptosis. Many cancer cells express Fas but do not undergo Fas-mediated apoptosis. Nitric oxide reverses this resistance by increasing levels of Fas at the plasma membrane. We studied the mechanisms by which NO affects Fas function. METHODS: Colon and mammary cancer cell lines were incubated with the NO donor glyceryl trinitrate or lipid A; S-nitrosylation of Fas was monitored using the biotin switch assay. Fas constructs that contained mutations at cysteine residues that prevent S-nitrosylation were used to investigate the involvement of S-nitrosylation in Fas-mediated cell death. Apoptosis was monitored according to morphologic criteria. RESULTS: NO induced S-nitrosylation of cysteine residues 199 and 304 in the cytoplasmic part of Fas. In cancer cells that overexpressed wild-type Fas, S-nitrosylation induced Fas recruitment to lipid rafts and sensitized the cells to Fas ligand. In cells that expressed a mutant form of Fas in which cysteine 304 was replaced by valine residue, NO-mediated translocation of Fas to lipid rafts was affected and the death-inducing signal complex and synergistic effect of glyceryl trinitrate-Fas ligand were inhibited significantly. These effects were not observed in cells that expressed Fas with a mutation at cysteine 199. CONCLUSIONS: We identified post-translational modifications (S-nitrosylation of cysteine residues 199 and 304) in the cytoplasmic domain of Fas. S-nitrosylation at cysteine 304 promotes redistribution of Fas to lipid rafts, formation of the death-inducing signal complex, and induction of cell death.

Dates et versions

hal-00680824 , version 1 (20-03-2012)

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Lissbeth Leon-Bollotte, Selvakumar Subramaniam, Olivier Cauvard, Stéphanie Plenchette-Colas, Catherine Paul, et al.. S-nitrosylation of the death receptor fas promotes fas ligand-mediated apoptosis in cancer cells.. Gastroenterology, 2011, 140 (7), pp.2009-18, 2018.e1-4. ⟨10.1053/j.gastro.2011.02.053⟩. ⟨hal-00680824⟩
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