Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFκB activation and cyclin D1 up-regulation

Yuan Soon Ho, Chien Ho Chen, Ying Jan Wang, Richard G. Pestell, Chris Albanese, Rong Jane Chen, Mei Chi Chang, Jiiang Huei Jeng, Shyr Yi Lin, Yu Chih Liang, How Tseng, Wen Sen Lee, Jen Kun Lin, Jan Show Chu, Li Ching Chen, Chia Hwa Lee, Wei Ling Tso, Yann Chwen Lai, Chih Hsiung Wu

Research output: Contribution to journalArticle

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Abstract

Cigarette smoke contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. Nicotine is one of the major components of the cigarette smoke and the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen. Here, we demonstrated that NNK stimulated cell proliferation in normal human bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). Cells exposed to NNK resulted in an increase in the level of cyclin D1 protein (as early as 3-6 h). Increased phosphorylation of the Rb Ser795 was detected at 6-15 h after NNK treatment and thereby promoted cells entering into the S phase (at 15-21 h). The increased cyclin D1 protein level was induced through activation of the transcription factor, nuclear factor kB (NFκB), in the NHBE cells. Treatment of the NHBE cells with PD98059, an ERK1/2 (extracellular signal-regulated protein kinase)-specific inhibitor, specifically suppressed the NNK-induced IκBα phosphorylation at position 32 of the serine residue, suggesting that the ERK1/2 kinase was involved in the IκBα phosphorylation induced by NFκB activation. To determine whether the NNK-induced NFκB activation and cyclin D1 induction were also observed in vivo, A/J mice were treated with NNK (9.1 mg) for 20 weeks and the results showed a significant induction of cyclin D1 and NFκB translocation determined by immunoblotting analyses. We further demonstrated that the nicotine acetylcholine receptor (nAchR), which contains the α3-subunit, was the major target mediating NNK-induced cyclin D1 expression in the NHBE cells. In summary, our findings demonstrate for the first time that NNK could stimulate normal human bronchial cell proliferation through activation of the NFκB, which in turn up-regulated the cyclin D1 expression.

Original languageEnglish
Pages (from-to)133-148
Number of pages16
JournalToxicology and Applied Pharmacology
Volume205
Issue number2
DOIs
Publication statusPublished - Jun 1 2005
Externally publishedYes

Fingerprint

Tobacco
Cyclin D1
Cell proliferation
Carcinogens
Up-Regulation
Epithelial Cells
Chemical activation
Cell Proliferation
Phosphorylation
Nicotine
Smoke
Tobacco Products
Mitogen-Activated Protein Kinase 3
Extracellular Signal-Regulated MAP Kinases
Cholinergic Receptors
Protein Kinase Inhibitors
S Phase
Immunoblotting
Protein Kinases
Serine

Keywords

  • Cyclin D1
  • Lung cancer
  • NFκB
  • Nicotine
  • NNK

ASJC Scopus subject areas

  • Pharmacology
  • Toxicology

Cite this

Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFκB activation and cyclin D1 up-regulation. / Ho, Yuan Soon; Chen, Chien Ho; Wang, Ying Jan; Pestell, Richard G.; Albanese, Chris; Chen, Rong Jane; Chang, Mei Chi; Jeng, Jiiang Huei; Lin, Shyr Yi; Liang, Yu Chih; Tseng, How; Lee, Wen Sen; Lin, Jen Kun; Chu, Jan Show; Chen, Li Ching; Lee, Chia Hwa; Tso, Wei Ling; Lai, Yann Chwen; Wu, Chih Hsiung.

In: Toxicology and Applied Pharmacology, Vol. 205, No. 2, 01.06.2005, p. 133-148.

Research output: Contribution to journalArticle

Ho, Yuan Soon ; Chen, Chien Ho ; Wang, Ying Jan ; Pestell, Richard G. ; Albanese, Chris ; Chen, Rong Jane ; Chang, Mei Chi ; Jeng, Jiiang Huei ; Lin, Shyr Yi ; Liang, Yu Chih ; Tseng, How ; Lee, Wen Sen ; Lin, Jen Kun ; Chu, Jan Show ; Chen, Li Ching ; Lee, Chia Hwa ; Tso, Wei Ling ; Lai, Yann Chwen ; Wu, Chih Hsiung. / Tobacco-specific carcinogen 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) induces cell proliferation in normal human bronchial epithelial cells through NFκB activation and cyclin D1 up-regulation. In: Toxicology and Applied Pharmacology. 2005 ; Vol. 205, No. 2. pp. 133-148.
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abstract = "Cigarette smoke contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. Nicotine is one of the major components of the cigarette smoke and the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen. Here, we demonstrated that NNK stimulated cell proliferation in normal human bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). Cells exposed to NNK resulted in an increase in the level of cyclin D1 protein (as early as 3-6 h). Increased phosphorylation of the Rb Ser795 was detected at 6-15 h after NNK treatment and thereby promoted cells entering into the S phase (at 15-21 h). The increased cyclin D1 protein level was induced through activation of the transcription factor, nuclear factor kB (NFκB), in the NHBE cells. Treatment of the NHBE cells with PD98059, an ERK1/2 (extracellular signal-regulated protein kinase)-specific inhibitor, specifically suppressed the NNK-induced IκBα phosphorylation at position 32 of the serine residue, suggesting that the ERK1/2 kinase was involved in the IκBα phosphorylation induced by NFκB activation. To determine whether the NNK-induced NFκB activation and cyclin D1 induction were also observed in vivo, A/J mice were treated with NNK (9.1 mg) for 20 weeks and the results showed a significant induction of cyclin D1 and NFκB translocation determined by immunoblotting analyses. We further demonstrated that the nicotine acetylcholine receptor (nAchR), which contains the α3-subunit, was the major target mediating NNK-induced cyclin D1 expression in the NHBE cells. In summary, our findings demonstrate for the first time that NNK could stimulate normal human bronchial cell proliferation through activation of the NFκB, which in turn up-regulated the cyclin D1 expression.",
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AU - Ho, Yuan Soon

AU - Chen, Chien Ho

AU - Wang, Ying Jan

AU - Pestell, Richard G.

AU - Albanese, Chris

AU - Chen, Rong Jane

AU - Chang, Mei Chi

AU - Jeng, Jiiang Huei

AU - Lin, Shyr Yi

AU - Liang, Yu Chih

AU - Tseng, How

AU - Lee, Wen Sen

AU - Lin, Jen Kun

AU - Chu, Jan Show

AU - Chen, Li Ching

AU - Lee, Chia Hwa

AU - Tso, Wei Ling

AU - Lai, Yann Chwen

AU - Wu, Chih Hsiung

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N2 - Cigarette smoke contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. Nicotine is one of the major components of the cigarette smoke and the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen. Here, we demonstrated that NNK stimulated cell proliferation in normal human bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). Cells exposed to NNK resulted in an increase in the level of cyclin D1 protein (as early as 3-6 h). Increased phosphorylation of the Rb Ser795 was detected at 6-15 h after NNK treatment and thereby promoted cells entering into the S phase (at 15-21 h). The increased cyclin D1 protein level was induced through activation of the transcription factor, nuclear factor kB (NFκB), in the NHBE cells. Treatment of the NHBE cells with PD98059, an ERK1/2 (extracellular signal-regulated protein kinase)-specific inhibitor, specifically suppressed the NNK-induced IκBα phosphorylation at position 32 of the serine residue, suggesting that the ERK1/2 kinase was involved in the IκBα phosphorylation induced by NFκB activation. To determine whether the NNK-induced NFκB activation and cyclin D1 induction were also observed in vivo, A/J mice were treated with NNK (9.1 mg) for 20 weeks and the results showed a significant induction of cyclin D1 and NFκB translocation determined by immunoblotting analyses. We further demonstrated that the nicotine acetylcholine receptor (nAchR), which contains the α3-subunit, was the major target mediating NNK-induced cyclin D1 expression in the NHBE cells. In summary, our findings demonstrate for the first time that NNK could stimulate normal human bronchial cell proliferation through activation of the NFκB, which in turn up-regulated the cyclin D1 expression.

AB - Cigarette smoke contains several carcinogens known to initiate and promote tumorigenesis as well as metastasis. Nicotine is one of the major components of the cigarette smoke and the 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone (NNK) is a tobacco-specific carcinogen. Here, we demonstrated that NNK stimulated cell proliferation in normal human bronchial epithelial cells (NHBE) and small airway epithelial cells (SAEC). Cells exposed to NNK resulted in an increase in the level of cyclin D1 protein (as early as 3-6 h). Increased phosphorylation of the Rb Ser795 was detected at 6-15 h after NNK treatment and thereby promoted cells entering into the S phase (at 15-21 h). The increased cyclin D1 protein level was induced through activation of the transcription factor, nuclear factor kB (NFκB), in the NHBE cells. Treatment of the NHBE cells with PD98059, an ERK1/2 (extracellular signal-regulated protein kinase)-specific inhibitor, specifically suppressed the NNK-induced IκBα phosphorylation at position 32 of the serine residue, suggesting that the ERK1/2 kinase was involved in the IκBα phosphorylation induced by NFκB activation. To determine whether the NNK-induced NFκB activation and cyclin D1 induction were also observed in vivo, A/J mice were treated with NNK (9.1 mg) for 20 weeks and the results showed a significant induction of cyclin D1 and NFκB translocation determined by immunoblotting analyses. We further demonstrated that the nicotine acetylcholine receptor (nAchR), which contains the α3-subunit, was the major target mediating NNK-induced cyclin D1 expression in the NHBE cells. In summary, our findings demonstrate for the first time that NNK could stimulate normal human bronchial cell proliferation through activation of the NFκB, which in turn up-regulated the cyclin D1 expression.

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