Abstract
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). Consistently, β-AR agonists led to increased IGF-1R phosphorylation. The increase in IGF2 transcription via β-AR, signal transducer and activator of transcription 3 (STAT3), and nuclear factor-kappa B (NF-κB) was associated with NNK-induced IGF-1R activation. Finally, treatment with β-AR antagonists suppressed the acquisition of transformed phenotypes in lung epithelial cells and lung tumor formation in mice. These results suggest that blocking β-AR-mediated IGF-1R activation can be an effective strategy for lung cancer prevention in smokers.
Highlights
Lung cancer is the main cause of cancer-related human death in Korea and worldwide [1,2,3]
We showed that NNK induced a rapid insulin-like growth factor 1 receptor (IGF-1R) activation in primary cultured normal human lung epithelial (HBE) cells derived from large airways, in various immortalized, normal Human bronchial epithelial (HBE) cell lines, including BEAS-2B, and in premalignant HBE cell line carrying loss of p53 expression (HBE/p53i)
We demonstrated that 1) β-adrenergic receptor (β-AR) mediates NNK-induced IGF-1R activation through the up-regulation of IGF2 transcription; 2) the Gβγ subunits dissociated from β-AR upon NNK exposure stimulate IGF-1R through the phospholipase C (PLC)-mediated pathway; and 3) the inhibition of β-AR
Summary
Lung cancer is the main cause of cancer-related human death in Korea and worldwide [1,2,3]. Drug resistance reduces the effectiveness of these targeted anticancer drugs [5], and the 5-year survival of lung cancer remains less than 20% [2] In this regard, cancer chemoprevention, an approach to prevent, retard or reverse the carcinogenic process using dietary or synthetic chemicals [6, 7], can be an effective strategy for controlling lung cancer. The chemoprevention trials for lung cancer to date have shown negative or somewhat harmful effects; currently, no agents have been identified to be effective for the prevention of lung cancer. These findings suggest the necessity to discover novel strategies to control lung cancer
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