Abstract
One of the key features of tumour cells is the acquisition of resistance to apoptosis. Thus, determining therapeutic strategies that circumvent apoptotic resistance and result in tumor regression is a challenge. One strategy to induce apoptosis is to activate death receptor signalling pathways. Members of the Tumor Necrosis Factor TNF-family death receptors ligand (TRAIL, FasL and TNF-α) can originate from immune and non-immune cells. Death receptors, engaged by cognate ligands, can initiate multiple signaling pathways, which can generate diverse outcomes, including non-apoptosis-related signal. Knowledge on the molecular mechanisms (that determine death or survival of tumour cells) following exposure to the TNF-family death receptors ligands have demonstrated that post-translational modifications of the signaling pathway components play a critical role in determining cell fate. Cell death can be sensed by nitric oxide (NO) in a wide variety of tumour cells. S-nitrosylation, the covalent modification of a protein cysteine thiol by an NO moiety, has emerged as an important post-translational regulation for the TNF-family death receptor signaling pathways. It has been demonstrated that death receptor DR4 (TRAIL-R1) becomes S-nitrosylated and promotes apoptosis following a specific NO donor treatment (Tang et al., 2006). Then, our group has shown that S-nitrosylation of Fas, following glyceryl trinitrate (GTN) exposure, promotes redistribution of the receptor to lipid rafts, formation of the death-inducing signal complex (DISC), and induction of cell death. Finally, I will discuss our recent efforts to decipher regulatory mechanism of the TNF-α/TNFR1 signalling cell death pathway by S-nitrosylation following GTN treatment.
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