Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation.
Bcl-2 is a key apoptosis regulatory protein of the mitochondrial death pathway. The oncogenic potential of Bcl-2 is well established, with its overexpression reported in various cancers. The antiapoptotic function of Bcl-2 is closely associated with its expression levels. Reactive oxygen and nitrogen species (ROS/RNS) are important intracellular signaling molecules that play a key role in various physiological processes including apoptosis. We have recently reported that ROS and RNS can regulate Bcl-2 expression levels, thereby impacting its function. Superoxide anion (*O(2)(-)) plays a proapoptotic role by causing downregulation and degradation of Bcl-2 protein through the ubiquitin-proteasomal pathway. In contrast, nitric oxide (NO)-mediated S-nitrosylation of Bcl-2 prevents its ubiquitination and subsequent proteasomal degradation, leading to inhibition of apoptosis. Interestingly, NO-mediated S-nitrosylation and stabilization of Bcl-2 protein was the primary mechanism involved in the malignant transformation of nontumorigenic lung epithelial cells in response to long-term carcinogen exposure. We describe a novel mechanism of Bcl-2 regulation by *O(2)(-) and NO, providing a new dimension to reactive species-mediated Bcl-2 stability, apoptotic cell death, and cancer development.
Azad
Neelam
N
Department of Pharmaceutical Sciences, School of Pharmacy, Hampton University, Hampton, Virginia, USA. neelam.azad@hamptonu.edu
Iyer
Anand
A
Vallyathan
Val
V
Wang
Liying
L
Castranova
Vincent
V
Stehlik
Christian
C
Rojanasakul
Yon
Y
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D016923:Cell Death / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D018384:Oxidative Stress / Q000235:genetics; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism* / Q000502:physiology; D026361:Reactive Nitrogen Species / Q000235:genetics / Q000502:physiology*; D013481:Superoxides / Q000378:metabolism*
D019253:Proto-Oncogene Proteins c-bcl-2; D026361:Reactive Nitrogen Species; D013481:Superoxides