Iyer Anand Krishnan V, Azad Neelam, Wang Liying, Rojanasakul Yon
Department of Pharmaceutical Sciences, West Virginia University, P.O. Box 9530, Morgantown, WV 26506, USA.
Nitric Oxide. 2008 Sep;19(2):146-51. doi: 10.1016/j.niox.2008.04.019. Epub 2008 Apr 24.
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.
一氧化氮（NO）通过调节各种信号转导途径中的重要蛋白质，已被广泛认为是肿瘤发生和癌症进展的正向调节因子。S-亚硝基化，即NO与蛋白质巯基的共价结合，已成为NO调节生理和病理细胞反应的重要机制。在本文中，我们讨论了内在和外在死亡途径的两种关键凋亡调节蛋白，即B细胞淋巴瘤-2（Bcl-2）和FLICE抑制蛋白（FLIP）的S-亚硝基化。这些蛋白在多种肿瘤中被证明上调，并通过凋亡失调与癌症化疗耐药性有关。这些蛋白的S-亚硝基化阻止了它们的泛素化以及随后被蛋白酶体降解，从而增强了它们的抗凋亡作用，这在肿瘤发生潜能和癌症进展的背景下至关重要。我们提出，NO对蛋白质的这种翻译后修饰可能是肿瘤细胞利用的一种普遍机制，通过逃避细胞死亡来向生存和增殖倾斜天平。
