Role of oxidative/nitrosative stress-mediated Bcl-2 regulation in apoptosis and malignant transformation

Ann N Y Acad Sci. 2010 Aug;1203:1-6. doi: 10.1111/j.1749-6632.2010.05608.x.

Abstract

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.

Publication types

  • Review

MeSH terms

  • Animals
  • Apoptosis / physiology*
  • Cell Death / genetics
  • Cell Survival / genetics
  • Cell Transformation, Neoplastic / genetics
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Gene Expression Regulation, Neoplastic
  • Humans
  • Lung Neoplasms / genetics
  • Lung Neoplasms / metabolism*
  • Lung Neoplasms / pathology
  • Oxidative Stress* / genetics
  • Proto-Oncogene Proteins c-bcl-2 / biosynthesis
  • Proto-Oncogene Proteins c-bcl-2 / genetics
  • Proto-Oncogene Proteins c-bcl-2 / metabolism*
  • Proto-Oncogene Proteins c-bcl-2 / physiology
  • Reactive Nitrogen Species / genetics
  • Reactive Nitrogen Species / physiology*
  • Superoxides / metabolism*

Substances

  • Proto-Oncogene Proteins c-bcl-2
  • Reactive Nitrogen Species
  • Superoxides