Nicotine enhances the antiapoptotic function of Mcl-1 through phosphorylation.
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.
Zhao
Jinfeng
J
National Hepatobiliary and Enteric Surgery Research Center, Department of Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, PR China.
Xin
Meiguo
M
Wang
Ton
T
Zhang
Yangde
Y
Deng
Xingming
X
D017209:Apoptosis / Q000187:drug effects*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D004789:Enzyme Activation / Q000187:drug effects; D005419:Flavonoids / Q000494:pharmacology; D006207:Half-Life; D006801:Humans; D008175:Lung Neoplasms / Q000201:enzymology / Q000473:pathology; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D009538:Nicotine / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D010769:Phosphothreonine / Q000378:metabolism; D011433:Propranolol / Q000494:pharmacology; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism*; D011943:Receptors, Adrenergic, beta / Q000378:metabolism
D005419:Flavonoids; D064549:Myeloid Cell Leukemia Sequence 1 Protein; D019253:Proto-Oncogene Proteins c-bcl-2; D011943:Receptors, Adrenergic, beta; D010769:Phosphothreonine; D009538:Nicotine; D011433:Propranolol; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one