Nicotine-induced cell survival is associated with chemoresistance of human lung 
cancer cells, but our understanding 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. 
granulocyte-macrophage colony-stimulating factor)-induced phosphorylation of Bax 
has been reported to negatively regulate its proapoptotic function. Because Bax 
is ubiquitously expressed in both small cell lung cancer and non-small cell lung 
cancer cells, nicotine may mimic growth factor(s) to regulate the activity of 
Bax. We found that nicotine potently induces Bax phosphorylation at Ser-184, 
which results in abrogation of the proapoptotic activity of Bax and increased 
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 phosphatidylinositol 3-kinase (PI3K) 
inhibitor LY294002 or specific depletion of AKT expression by RNA interference 
can block both nicotine-induced Bax phosphorylation and cell survival. 
Importantly, nicotine-induced Bax phosphorylation 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 
9-12 h to <6 h). Because knockdown of Bax expression by gene silencing results 
in prolonged cell survival following treatment with cisplatin in the absence or 
presence of nicotine, Bax may be an essential component in the nicotine survival 
signaling pathway. Thus, nicotine-induced survival and chemoresistance of human 
lung cancer cells may occur in a novel mechanism involving activation of 
PI3K/AKT that directly phosphorylates and inactivates the proapoptotic function 
of Bax.