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; Ho Young Lee

doi:10.1038/ncomms12961

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, Ho Young Lee

Translational Molecular Pathology

Research output: Contribution to journal › Article › peer-review

28 Scopus citations

Abstract

Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca 2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca 2+ 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 Ca 2+ 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.

Original language	English (US)
Article number	12961
Journal	Nature communications
Volume	7
DOIs	https://doi.org/10.1038/ncomms12961
State	Published - Sep 26 2016

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Boo, H. J., Min, H. Y., Jang, H. J., Yun, H. J., Smith, J. K., Jin, Q., Lee, H. J., Liu, D., Kweon, H. S., Behrens, C., Lee, J. J., Wistuba, I. I., Lee, E., Hong, W. K., & Lee, H. Y. (2016). The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells. Nature communications, 7, Article 12961. https://doi.org/10.1038/ncomms12961

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

abstract = "Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca 2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca 2+ 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 Ca 2+ 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.",

author = "Boo, {Hye Jin} and Min, {Hye Young} and Jang, {Hyun Ji} and Yun, {Hye Jeong} and Smith, {John Kendal} and Quanri Jin and Lee, {Hyo Jong} and Diane Liu and Kweon, {Hee Seok} and Carmen Behrens and Lee, {J. Jack} and Wistuba, {Ignacio I.} and Euni Lee and Hong, {Waun Ki} and Lee, {Ho Young}",

note = "Funding Information: This work was supported by a grant from the National Research Foundation of Korea (NRF), the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea (No. NRF-2016R1A3B1908631). Publisher Copyright: {\textcopyright} The Author(s) 2016.",

year = "2016",

month = sep,

day = "26",

doi = "10.1038/ncomms12961",

language = "English (US)",

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T1 - The tobacco-specific carcinogen-operated calcium channel promotes lung tumorigenesis via IGF2 exocytosis in lung epithelial cells

AU - Boo, Hye Jin

AU - Min, Hye Young

AU - Jang, Hyun Ji

AU - Yun, Hye Jeong

AU - Smith, John Kendal

AU - Jin, Quanri

AU - Lee, Hyo Jong

AU - Liu, Diane

AU - Kweon, Hee Seok

AU - Behrens, Carmen

AU - Lee, J. Jack

AU - Wistuba, Ignacio I.

AU - Lee, Euni

AU - Hong, Waun Ki

AU - Lee, Ho Young

N1 - Funding Information: This work was supported by a grant from the National Research Foundation of Korea (NRF), the Ministry of Science, ICT & Future Planning (MSIP), Republic of Korea (No. NRF-2016R1A3B1908631). Publisher Copyright: © The Author(s) 2016.

PY - 2016/9/26

Y1 - 2016/9/26

N2 - Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca 2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca 2+ 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 Ca 2+ 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.

AB - Nicotinic acetylcholine receptors (nAChRs) binding to the tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces Ca 2+ signalling, a mechanism that is implicated in various human cancers. In this study, we investigated the role of NNK-mediated Ca 2+ 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 Ca 2+ 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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ER -

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

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