摘要：

Nicotine-induced cell survival is associated with chemoresistance of human lung cancer cells but ourunderstanding of the intracellular mechanism(s) is fragmentary. Bax is a major proapoptotic member of the Bcl2 family and a molecule required for apoptotic cell death. Growth factor (i.e. GM-CSF)-inducedphosphorylation of Bax has been reported to negatively regulate its proapoptotic function. Since Bax isubiquitously expressed in both small-cell lung cancer (SCLC) and non-small-cell lung cancer (NSCLC)cells, nicotine may mimic growth factor(s) to regulate Bax's activity. We found that nicotine potentlyinduces Bax phosphorylation at ser184, which results in abrogation of Bax's proapoptotic activity andincreased cell survival. AKT, a known physiological Bax kinase, is activated by nicotine, co-localizes with Bax in the cytoplasm and can directly phosphorylate Bax in vitro. Treatment of cells with the PI3Kinhibitor LY294002 or specific depletion of AKT expression by RNA interference (RNAi) can block both nicotine-induced Bax phosphorylation and cell survival. Importantly, nicotine-induced Baxphosphorylation potently blocks stress-induced translocation of Bax from cytosol to mitochondria,impairs Bax insertion into mitochondrial membranes and reduces the half-life of Bax protein (i.e. from 9- 12h to < 6h). Since knockdown of Bax expression by gene silencing results in prolonged cell survivalfollowing treatment with cisplatin in the absence or presence of nicotine, Bax may be an essentialcomponent in the nicotine survival signaling pathway. Thus, nicotine-induced survival andchemoresistance of human lung cancer cells may occur in a novel mechanism involving activation ofPI3K/AKT that directly phosphorylates and inactivates Bax's proapoptotic function.

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