한빛사논문
Abstract
Hye-Jin Boo1, Hye-Young Min1,2, Hyun-Ji Jang1, Hye Jeong Yun1, John Kendal Smith3, Quanri Jin3, Hyo-Jong Lee3, Diane Liu4, Hee-Seok Kweon5, Carmen Behrens3, J. Jack Lee4, Ignacio I. Wistuba3,6, Euni Lee7, Waun Ki Hong3 & Ho-Young Lee1,2,7,*
1 Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea. 2 Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Suwon, Gyeonggi 16229, Republic of Korea. 3 Departments of Thoracic/Head & Neck Medical Oncology, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 4 Department of Biostatics, The University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 5 Division of Electron Microscopic Research, Korea Basic Science Institute, Daejeon 34133, Republic of Korea. 6 Departments of Pathology, The
University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA. 7 Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea.
*Correspondence and requests for materials should be addressed to H.-Y.L.
Abstract
Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca2+ 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. NNK induces voltage-dependent calcium channel (VDCC)-intervened calcium influx in airway epithelial cells, resulting in a rapid IGF2 secretion via the regulated pathway and thus IGF-1R activation. Silencing nAChR, α1 subunit of L-type VDCC, or various vesicular trafficking curators, including synaptotagmins and Rabs, or blockade of nAChR/VDCC-mediated Ca2+ influx significantly suppresses NNK-induced IGF2 exocytosis, transformation and tumorigenesis of lung epithelial cells. Publicly available database reveals inverse correlation between use of calcium channel blockers and lung cancer diagnosis. Our data indicate that NNK disrupts the regulated pathway of IGF2 exocytosis and promotes lung tumorigenesis.
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