Tobacco specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone suppresses a newly identified anti-tumor IGFBP-3/IGFBP-3R system in lung cancer cells

IGFBP-3 is a tumor suppressor whose expression is frequently suppressed in lung cancer. NNK, the most potent tobacco carcinogen, enhanced cell proliferation of BEAS-2B normal lung epithelial cells and concomitantly suppressed IGFBP-3 expression through DNA methylation. Decreased IGFBP-3 expression and elevated levels of phospho-Akt, phospho-p65-NF-κB, and cyclin D1 were detected in tobacco carcinogen-induced tumorigenic derivatives of BEAS-2B. Overexpression of IGFBP-3 in NNKA, one of the derivatives, suppressed NF-κB activity and induced apoptosis, which was hindered by knocking-down of endogenous IGFBP-3R, an IGFBP-3 specific receptor. These results suggest that NNK inhibits IGFBP-3 expression to abrogate anti-tumor actions of the IGFBP-3/IGFBP-3R system in smoking-induced lung cancer.