Role Of S-Nitrosylation In The Extrinsic Apoptotic Signalling Pathway In Cancer.

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.