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Mol Cancer Res. 2009 Dec;7(12):1954-61. doi: 10.1158/1541-7786.MCR-09-0304. Epub 2009 Nov 10.

Nicotine enhances the antiapoptotic function of Mcl-1 through phosphorylation.

Author information

1
National Hepatobiliary and Enteric Surgery Research Center, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.

Abstract

Lung cancer has a strong etiologic 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 and non-small cell lung cancer 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 extracellular signal-regulated kinase 1/2 in association with increased chemoresistance of human lung cancer cells. Since nicotine stimulates Mcl-1 phosphorylation and survival in cells expressing wild-type but has no such effects in cells expressing T163A Mcl-1 mutant, this indicates that nicotine induces Mcl-1 phosphorylation exclusively at the T163 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 interference blocks 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.

PMID:
19903766
PMCID:
PMC2796280
DOI:
10.1158/1541-7786.MCR-09-0304
[Indexed for MEDLINE]
Free PMC Article

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