Lung tumorigenesis promoted by anti-apoptotic effects of cotinine, a nicotine metabolite through activation of PI3K/Akt pathway

• Nakada Tomohisa

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Kiyotani Kazuma

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Iwano Shunsuke

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Uno Takahiko

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Yokohira Masanao

  Faculty of Medicine, Kagawa University

• Yamakawa Keiko

  Faculty of Medicine, Kagawa University

• Fujieda Masaki

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Saito Tetsuya

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University

• Yamazaki Hiroshi

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University Showa Pharmaceutical University

• Imaida Katsumi

  Faculty of Medicine, Kagawa University

• Kamataki Tetsuya

  Laboratory of Drug Metabolism, Graduate School of Pharmaceutical Sciences, Hokkaido University Showa Pharmaceutical University

抄録

We previously found that genetic polymorphism in cytochrome P450 2A6 (CYP2A6) is one of the potential determinants of tobacco-related lung cancer risk. It has been reported that the plasma concentration of cotinine, a major metabolite of nicotine, in carriers of wild-type alleles of CYP2A6 is considerably higher than that in carriers of null or reduced-function alleles of CYP2A6, raising the possibility that cotinine plays an important role in the development of lung cancer. As a novel mechanism of lung tumorigenesis mediated by CYP2A6, we investigated the effects of cotinine on the suppression of apoptosis and promotion of lung tumor growth. In human lung adenocarcinoma A549 cells, cotinine inhibited doxorubicin-induced cell death by suppressing caspase-mediated apoptosis. Enhanced phosphorylation of Akt, a key factor responsible for cell survival and inhibition of apoptosis, was detected after cotinine treatment. These data suggest that cotinine suppresses caspase-mediated apoptosis induced by doxorubicin through activation of the PI3K/Akt pathway. Furthermore, we clarified that cotinine significantly facilitated tumor growth in the Lewis lung cancer model and accelerated development of lung adenomas induced by 4-(methylnitrosamino)-1-(3-pyridyl)-1-butanone in A/J mice. We herein propose that cotinine induces tumor promotion by inhibiting apoptosis and enhancing cellular proliferation, thus underlining the importance of CYP2A6 in tobacco-related lung tumorigenesis.

収録刊行物

• Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ

  Ｔｈｅ　Ｊｏｕｒｎａｌ　ｏｆ　Ｔｏｘｉｃｏｌｏｇｉｃａｌ　Ｓｃｉｅｎｃｅｓ 37 (3), 555-563, 2012

  一般社団法人　日本毒性学会

キーワード

• P450 2A6
• Lung cancer
• Tobacco smoking
• Apoptosis
• Nicotine

詳細情報

• CRID: 1390282679881019136
• NII論文ID: 130004446976
• NII論文ID: 10030436245
• NII書誌ID: AN00002808
• DOI: 10.2131/jts.37.555
• COI: 1:CAS:528:DC%2BC38XhtFajur3I
• ISSN: 18803989
• ISSN: 03881350
• NDL書誌ID: 023833049
• PubMed: 22687995
• Web Site: https://ndlsearch.ndl.go.jp/books/R000000004-I023833049
• Web Site: https://www.jstage.jst.go.jp/article/jts/37/3/37_555/_pdf
• Web Site: https://search.jamas.or.jp/link/ui/2013137225
• 本文言語コード: en
• データソース種別:
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  • NDL
  • Crossref
  • PubMed
  • CiNii Articles
  • KAKEN
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