Smoking-associated lung cancer prevention by blockade of the beta-adrenergic receptor-mediated insulin-like growth factor receptor activation
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Hye-Young Min1,2,*, Hye-Jin Boo1,*, Ho Jin Lee1,*, Hyun-Ji Jang1, Hye Jeong Yun1, Su Jung Hwang3, John Kendal Smith4, Hyo-Jong Lee3, Ho-Young Lee1,2,5,6
1Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
2Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Republic of Korea
3College of Pharmacy, Inje University, Gimhae 50834, Republic of Korea
4Department of Thoracic Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA
5College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea
6Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea
*These authors have contributed equally to this work
Ho-Young Lee, email: firstname.lastname@example.org
Keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone, insulin-like growth factor 1 receptor, insulin-like growth factor 2, β-adrenergic receptor, lung cancer
Received: October 13, 2015 Accepted: August 21, 2016 Published: September 29, 2016
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.
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