Role of S-nitrosylation in apoptosis resistance and carcinogenesis.
Nitric oxide (NO) has been widely recognized as a positive regulator of tumorigenesis and cancer progression through its ability to regulate important proteins in various signal transduction pathways. S-Nitrosylation, or covalent attachment of NO to protein sulphydryl groups, has gained prominence as an important mechanism by which NO modulates physiologic and pathologic cellular responses. In this article, we discuss S-nitrosylation of two key apoptosis-regulatory proteins of the intrinsic and extrinsic death pathways, namely B-cell lymphoma-2 (Bcl-2) and FLICE-inhibitory protein (FLIP). These proteins have been shown to be upregulated in a variety of tumors and have been implicated with cancer chemoresistance through dysregulation of apoptosis. S-Nitrosylation of these proteins precludes their ubiquitination and subsequent degradation by the proteasome, thus accentuating their anti-apoptotic effect which is critical in the context of tumorigenic potential and cancer progression. We propose that such post-translational modifications of proteins by NO may be a general mechanism that tumor cells exploit to tilt the scales towards survival and proliferation by evading cell death.
Iyer
Anand Krishnan V
AK
Department of Pharmaceutical Sciences, West Virginia University, P.O. Box 9530, Morgantown, WV 26506, USA.
Azad
Neelam
N
Wang
Liying
L
Rojanasakul
Yon
Y
D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism*; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein / Q000378:metabolism; D002470:Cell Survival; D002471:Cell Transformation, Neoplastic / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D009569:Nitric Oxide / Q000378:metabolism* / Q000502:physiology; D011499:Protein Processing, Post-Translational / Q000502:physiology*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism
D051017:Apoptosis Regulatory Proteins; D053446:CASP8 and FADD-Like Apoptosis Regulating Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D009569:Nitric Oxide