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

Hye-Jin Boo, Hye-Young Min, Hyun-Ji Jang, Hye Jeong Yun, John Kendal Smith, Quanri Jin, Hyo-Jong Lee, Diane Liu, Hee-Seok Kweon, Carmen Behrens, J. Jack Lee, Ignacio I. Wistuba, Euni Lee, Waun Ki Hong and Ho-Young Lee ()
Additional contact information
Hye-Jin Boo: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University
Hye-Young Min: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University
Hyun-Ji Jang: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University
Hye Jeong Yun: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University
John Kendal Smith: The University of Texas M.D. Anderson Cancer Center
Quanri Jin: The University of Texas M.D. Anderson Cancer Center
Hyo-Jong Lee: The University of Texas M.D. Anderson Cancer Center
Diane Liu: The University of Texas M.D. Anderson Cancer Center
Hee-Seok Kweon: Korea Basic Science Institute
Carmen Behrens: The University of Texas M.D. Anderson Cancer Center
J. Jack Lee: The University of Texas M.D. Anderson Cancer Center
Ignacio I. Wistuba: The University of Texas M.D. Anderson Cancer Center
Euni Lee: Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University
Waun Ki Hong: The University of Texas M.D. Anderson Cancer Center
Ho-Young Lee: Creative Research Initiative Center for Concurrent Control of Emphysema and Lung Cancer, College of Pharmacy, Seoul National University

Nature Communications, 2016, vol. 7, issue 1, 1-16

Abstract: 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.

Date: 2016
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DOI: 10.1038/ncomms12961

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