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Research ArticleArticle

Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis

Satoki Karasawa, Motoki Azuma, Takeshi Kasama, Satoshi Sakamoto, Yasuaki Kabe, Takeshi Imai, Yuki Yamaguchi, Keisuke Miyazawa and Hiroshi Handa
Molecular Pharmacology March 2013, 83 (3) 613-620; DOI: https://doi.org/10.1124/mol.112.082602
Satoki Karasawa
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Motoki Azuma
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Takeshi Kasama
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Satoshi Sakamoto
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Yasuaki Kabe
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Takeshi Imai
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Yuki Yamaguchi
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Keisuke Miyazawa
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Hiroshi Handa
Department of Biological Information, Graduate School of Bioscience and Biotechnology, Tokyo Institute of Technology, Yokohama, Japan (S.K., M.A., S.S., Y.Y., H.H.); Instrumental Analysis Research Division, Research Center for Medical and Dental Sciences, Tokyo Medical and Dental University, Tokyo, Japan (T.K.); Department of Biochemistry, School of Medicine, Keio University, Tokyo, Japan (Y.K.); Biofrontier Center, Tokyo Institute of Technology, Yokohama, Japan (T.I.); Department of Biochemistry, Tokyo Medical University, Tokyo, Japan (K.M.)
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Abstract

Vitamin K2 (VK2, menaquinone) is known to have anticancer activity in vitro and in vivo. Although its effect is thought to be mediated, at least in part, by the induction of apoptosis, the underlying molecular mechanism remains elusive. Here, we identified Bcl-2 antagonist killer 1 (Bak) as a molecular target of VK2-induced apoptosis. VK2 directly interacts with Bak and induces mitochondrial-mediated apoptosis. Although Bak and Bcl-2-associated X protein (Bax), another member of the Bcl-2 family, are generally thought to be functionally redundant, only Bak is necessary and sufficient for VK2-induced cytochrome c (cyt c) release and cell death. Moreover, VK2-2,3 epoxide, an intracellular metabolite of VK2, was shown to covalently bind to the cysteine-166 residue of Bak. Several lines of evidence suggested that the covalent attachment of VK2 is critical for apoptosis induction. Thus this study reveals a specific role for Bak in mitochondria-mediated apoptosis. This study also provides insight into the anticancer effects of VK2 and suggests that Bak may be a potential target of cancer therapy.

Footnotes

  • This work was supported by a Grant-in-Aid for Scientific Research on Innovative areas “Chemical Biology of Natural Products” from The Ministry of Education, Culture, Sports, Science and Technology, Japan.

  • dx.doi.org/10.1124/mol.112.082602.

  • ↵Embedded ImageThis article has supplemental material available at molpharm.aspetjournals.org.

  • Received September 22, 2012.
  • Accepted December 10, 2012.
  • Copyright © 2013 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 83 (3)
Molecular Pharmacology
Vol. 83, Issue 3
1 Mar 2013
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Research ArticleArticle

Bak as a Molecular Target of Vitamin K2-Induced Apoptosis

Satoki Karasawa, Motoki Azuma, Takeshi Kasama, Satoshi Sakamoto, Yasuaki Kabe, Takeshi Imai, Yuki Yamaguchi, Keisuke Miyazawa and Hiroshi Handa
Molecular Pharmacology March 1, 2013, 83 (3) 613-620; DOI: https://doi.org/10.1124/mol.112.082602

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Research ArticleArticle

Bak as a Molecular Target of Vitamin K2-Induced Apoptosis

Satoki Karasawa, Motoki Azuma, Takeshi Kasama, Satoshi Sakamoto, Yasuaki Kabe, Takeshi Imai, Yuki Yamaguchi, Keisuke Miyazawa and Hiroshi Handa
Molecular Pharmacology March 1, 2013, 83 (3) 613-620; DOI: https://doi.org/10.1124/mol.112.082602
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