NNK-induced hamster lung adenocarcinomas over-express β2-adrenergic and EGFR signaling pathways

Our immunohistochemical analysis of NNK-induced PAC in hamsters demonstrates the simultaneous over-expression of a β2-adrenergic receptor pathway, including PKA, cAMP, CREB and phosphorylated CREB and of an EGFR pathway, including over-expression of EGFR-specific phosporylated tyrosine kinase, Raf-1 and ERK1/2 and their phosphorylated forms. These findings implicate, for the first time, PKA/CREB-mediated signaling in the development and regulation of any type of lung cancer. In light of reports that NNK acts as a β-adrenergic agonist and that β-blockers inhibit the growth of PAC of Clara cell lineage in the NNK hamster model and in human cancer cell lines from smokers, our current data suggest transactivation of the EGFR pathway via β-adrenergic signaling as a novel regulatory mechanism in a subpopulation of PACs in smokers. Taken together, these data point to PKA/CREB as novel targets for the development of cancer therapeutics for PAC patients non-responsive to EGFR-specific tyrosine kinase inhibitors.