Abstract
Lung cancer is the leading cause of cancer death and has a strong etiological association with cigarette smoking. Nicotine and nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are two major components in cigarette smoke that significantly contribute to the development of human lung cancer. Nicotine is able to stimulate survival of both normal human lung epithelial and lung cancer cells. In contrast to nicotine, NNK is a more potent carcinogen that not only induces single-strand DNA breaks and oxidative DNA damage but also stimulates survival and proliferation of normal lung epithelial and lung cancer cells. However, the molecular mechanism(s) by which nicotine and NNK promote cell survival, proliferation, and lung tumor development remains elusive. The fate of cells (i.e., survival or death) is largely decided by the Bcl2 family members. In the past several years, multiple signaling links between nicotine/NNK and Bcl2 family members have been identified that regulate survival and proliferation. This review provides a concise, systematic overview of the current understanding of the role of the pro- or antiapoptotic proteins in cigarette smoking, lung cancer development, and treatment resistance.
Highlights
The best currently available therapies for lung cancer patients achieve overall 5-year survival rates of 16% and 6% for NSCLC and SCLC, respectively [1]
We have identified that ERK1/2 functions as a physiologic staurosporineresistant Bcl2 kinase (SRK) that is able to induce Bcl2 phosphorylation at S70 in vitro and in vivo [37]
We recently discovered that nicotine promotes survival of human lung cancer cells through a novel mechanism by activating the antiapoptotic function of Mcl-1 via its phosphorylation [23]
Summary
The best currently available therapies for lung cancer patients achieve overall 5-year survival rates of 16% and 6% for NSCLC and SCLC, respectively [1]. We have recently discovered that the cigarette smoke components, nicotine and NNK, can induce phosphorylation of Bcl2, Mcl-1, Bax, and Bad, which leads to activation of Bcl2 and Mcl-1 [5, 23] and inactivation of Bax and Bad in association with increased chemoresistance in human lung cancer cells [24, 25]. Nicotine has been reported to activate a protein kinase cascade (i.e., PKC/Raf/MEK/ERKs) that may potentially promote survival and proliferation of human lung cancer cells [32,33,34,35,36].
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