Smoking-associated lung cancer prevention by blockade of the beta-adrenergic receptor-mediated insulin-like growth factor receptor activation.

Activation of receptor tyrosine kinases (RTKs) is associated with carcinogenesis, but its contribution to smoking-associated lung carcinogenesis is poorly understood. Here we show that a tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK)-induced insulin-like growth factor 1 receptor (IGF-1R) activation via β-adrenergic receptor (β-AR) is crucial for smoking-associated lung carcinogenesis. Treatment with NNK stimulated the IGF-1R signaling pathway in a time- and dose-dependent manner, which was suppressed by pharmacological or genomic blockade of β-AR and the downstream signaling including a Gβγ subunit of β-AR and phospholipase C (PLC).

The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells.

Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca signalling in lung cancer formation. We show significant overexpression of insulin-like growth factors (IGFs) in association with IGF-1R activation in human preneoplastic lung lesions in smokers.

Transcriptional and posttranslational regulation of insulin-like growth factor binding protein-3 by Akt3.

Insulin-like growth factor (IGF)-dependent and -independent antitumor activities of insulin-like growth factor binding protein-3 (IGFBP-3) have been proposed in human non-small cell lung cancer (NSCLC) cells. However, the mechanism underlying regulation of IGFBP-3 expression in NSCLC cells is not well understood. In this study, we show that activation of Akt, especially Akt3, plays a major role in the mRNA expression and protein stability of IGFBP-3 and thus antitumor activities of IGFBP-3 in NSCLC cells.