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

被引：34

作者：

Boo, Hye-Jin ^{[1
]}

Min, Hye-Young ^{[1
,2
]}

Jang, Hyun-Ji ^{[1
]}

Yun, Hye Jeong ^{[1
]}

Smith, John Kendal ^{[3
]}

Jin, Quanri ^{[3
]}

Lee, Hyo-Jong ^{[3
]}

Liu, Diane ^{[4
]}

Kweon, Hee-Seok ^{[5
]}

Behrens, Carmen ^{[3
]}

Lee, J. Jack ^{[4
]}

Wistuba, Ignacio I. ^{[3
,6
]}

Lee, Euni ^{[7
]}

Hong, Waun Ki ^{[3
]}

Lee, Ho-Young ^{[1
,2
,7
]}

机构：

[1] Seoul Natl Univ, Coll Pharm, Creat Res Initiat, Ctr Concurrent Control Emphysem, Seoul 08826, South Korea

[2] Seoul Natl Univ, Grad Sch Convergence Sci & Technol, Dept Mol Med & Biopharmaceut Sci, Suwon 16229, Gyeonggi, South Korea

[3] Univ Texas MD Anderson Canc Ctr, Dept Thorac Head & Neck Med Oncol, Houston, TX 77030 USA

[4] Univ Texas MD Anderson Canc Ctr, Dept Biostat, Houston, TX 77030 USA

[5] Korea Basic Sci Inst, Div Electron Microscop Res, Daejeon 34133, South Korea

[6] Univ Texas MD Anderson Canc Ctr, Dept Pathol, Houston, TX 77030 USA

[7] Seoul Natl Univ, Pharmaceut Sci Res Inst, Coll Pharm, Seoul 08826, South Korea

来源：

NATURE COMMUNICATIONS | 2016年 / 7卷

基金：

新加坡国家研究基金会;

关键词：

GROWTH-FACTOR-I; NICOTINIC ACETYLCHOLINE-RECEPTORS; AKT ACTIVATION; CANCER-CELLS; RAB GTPASES; SRC FAMILY; INSULIN; BINDING; RISK; 4-(METHYLNITROSAMINO)-1-(3-PYRIDYL)-1-BUTANONE;

D O I：

10.1038/ncomms12961

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

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, alpha 1 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.

引用

页数：16

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