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Nicotine Enhances the Antiapoptotic Function of Mcl-1 through Phosphorylation

Authors
Keywords
  • Health Sciences
  • Oncology
Disciplines
  • Biology
  • Medicine

Abstract

Lung cancer has a strong etiological association with cigarette smoking. Nicotine, a major component in tobacco smoke, functions as a survival agonist that inhibits apoptosis following various stresses. However, the mechanism of action remains elusive. Mcl-1, a major antiapoptotic protein of the Bcl2 family, is extensively expressed in both small cell (SCLC) and non-small cell lung cancer (NSCLC) cells, suggesting that Mcl-1 may be a therapeutic target of patients with lung cancer. Here we found that nicotine induces Mcl-1 phosphorylation through activation of ERK1/2 in association with increased chemoresistance of human lung cancer cells. Since nicotine stimulates Mcl-1 phosphorylation and survival in cells expressing WT but has no such effects in cells expressing T163A Mcl-1 mutant, this indicates that nicotine induces Mcl-1 phosphorylation exclusively at the T 163 site and that phosphorylation of Mcl-1 at T163 is required for nicotine-induced survival. Mechanistically, nicotine-induced Mcl-1 phosphorylation significantly enhances the half-life of Mcl-1, which renders Mcl-1 a long-term survival activity. Specific depletion of Mcl-1 by RNA interferenceblocks nicotine-stimulated survival and enhances apoptotic cell death. Thus, nicotine-enhanced survival of lung cancer cells may occur through activation of Mcl-1 by phosphorylation at T163 site, which may contribute to development of human lung cancer and/or chemoresistance.

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