title: Smoking-associated lung cancer prevention by blockade of the beta-adrenergic receptor-mediated insulin-like growth factor receptor activation.
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.
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Republic of Korea.
authors.forename: Hye-Young
authors.initials: HY
authors.lastname: Min
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hye-Jin
authors.initials: HJ
authors.lastname: Boo
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Ho Jin
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hyun-Ji
authors.initials: HJ
authors.lastname: Jang
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Hye Jeong
authors.initials: HJ
authors.lastname: Yun
authors.affiliation: College of Pharmacy, Inje University, Gimhae 50834, Republic of Korea.
authors.forename: Su Jung
authors.initials: SJ
authors.lastname: Hwang
authors.affiliation: Department of Thoracic Head & Neck Medical Oncology, The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030, USA.
authors.forename: John Kendal
authors.initials: JK
authors.lastname: Smith
authors.affiliation: College of Pharmacy, Inje University, Gimhae 50834, Republic of Korea.
authors.forename: Hyo-Jong
authors.initials: HJ
authors.lastname: Lee
authors.affiliation: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.|Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon 16229, Republic of Korea.|College of Pharmacy and Research Institute of Pharmaceutical Sciences, Seoul National University, Seoul 08826, Republic of Korea.|Interdisciplinary Program in Genetic Engineering, Seoul National University, Seoul 08826, Republic of Korea.
authors.forename: Ho-Young
authors.initials: HY
authors.lastname: Lee
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology; D000319:Adrenergic beta-Antagonists / Q000494:pharmacology; D000818:Animals; D063646:Carcinogenesis / Q000139:chemically induced / Q000473:pathology*; D002273:Carcinogens / Q000494:pharmacology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004305:Dose-Response Relationship, Drug; D005260:Female; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D007335:Insulin-Like Growth Factor II / Q000235:genetics / Q000378:metabolism; D008175:Lung Neoplasms / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control*; D051379:Mice; D016328:NF-kappa B / Q000378:metabolism; D009374:Neoplasms, Experimental / Q000139:chemically induced / Q000473:pathology / Q000517:prevention & control; D009602:Nitrosamines / Q000494:pharmacology*; D010766:Phosphorylation / Q000187:drug effects; D017526:Receptor, IGF Type 1; D011943:Receptors, Adrenergic, beta / Q000378:metabolism*; D017451:Receptors, Somatomedin / Q000378:metabolism*; D050796:STAT3 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D012907:Smoking / Q000009:adverse effects*; D047368:Tumor Burden
chemical_list: D000318:Adrenergic beta-Agonists; D000319:Adrenergic beta-Antagonists; D002273:Carcinogens; C000597236:IGF1R protein, human; C035170:IGF2 protein, human; D016328:NF-kappa B; D009602:Nitrosamines; D011943:Receptors, Adrenergic, beta; D017451:Receptors, Somatomedin; D050796:STAT3 Transcription Factor; C494086:STAT3 protein, human; D007335:Insulin-Like Growth Factor II; C016583:4-(N-methyl-N-nitrosamino)-1-(3-pyridyl)-1-butanone; D017526:Receptor, IGF Type 1
keywords: 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone; insulin-like growth factor 1 receptor; insulin-like growth factor 2; lung cancer; β-adrenergic receptor