Lung cancer is the predominant cause of cancer deaths worldwide and has a strong etiological association with cigarette smoking. Nicotine and nitrosamine 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) are two important components in cigarette smoke. Nicotine can activate the growth-promoting pathways to facilitate the development of lung cancer. NNK is formed by nitrosation of nicotine and has been identified as the most potent carcinogen in cigarette smoke. We have recently demonstrated that nicotine induces Bcl2 phosphorylation exclusively at serine70 through activation of ERK1/2 in association with prolonged survival of small cell lung cancer (SCLC) cells. Thus, nicotine-induced cell survival results, at least in part, from a mechanism that involves Bcl2 phosphorylation. c-Myc is a major oncogenic protein that can functionally cooperate with Bcl2 in cell proliferation, transformation, apoptosis and tumorigenicity. Our preliminary data indicate that nicotine and NNK simultaneously induces Bcl2 and c-Myc phosphorylation in association with increased proliferation of SCLC cells but the intracellular mechanism(s) remains unclear. Bcl2 and c-Myc are expressed in both normal lung epithelial and lung cancer cells. These two oncoproteins may function as the oncogenic targets of nicotine or NNK-activated signal pathways. NNK can directly induce single strand DNA breaks and increases reactive oxygen species (ROS) that cause oxidative DNA damage. Since both Bcl2 and c-Myc function to promote genomic instability, Bcl2 may overcome the apoptotic effect from c-Myc and synergize with c-Myc to attenuate DNA repair and retain NNK-induced DNA damage in surviving cells, which may contribute to tumorigenesis. To critically test these hypotheses, we have identified two specific aims: (1) To determine if and how nicotine- or NNK- induced phosphorylation of Bcl2 and c-Myc can promote their cooperation in regulating survival and proliferation of human lung cancer cells. Studies will identify the mechanism(s) for the direct interaction between Bcl2 md c-Myc; (2) To determine whether the functional cooperation between Bcl2 and c-Myc is required for nicotine- or NNK-induced survival, proliferation and retaining NNK-induced DNA damage and genetic instability in both normal lung epithelial and lung cancer cells. Studies will identify novel mechanism(s) by which Bcl2 may functionally cooperate with c-Myc through phosphorylation at both the nuclear and mitochondrial levels. State of the art molecular and biochemical methodologies will be employed including site-directed gene mutagenesis, RNA interference or gene silencing. The results are expected to fill in fundamental gaps in our knowledge regarding the signaling and oncogenic mechanisms by which nicotine and NNK regulate Bcl2, c-Myc, proliferation and the genetic instability in both normal lung epithelial and lung cancer cells. Results from these studies are expected to have potential clinical relevance for the treatment of tobacco-related cancer specifically lung or other Bcl2 and c-Myc expressing malignancies and may contribute significantly to the development of novel strategies specifically aimed at functionally disrupting the oncogenic cooperation between Bcl2 and c-Myc.

National Institute of Health (NIH)
National Cancer Institute (NCI)
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Cancer Etiology Study Section (CE)
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Poland, Alan P
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University of Florida
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