PT  - JOURNAL ARTICLE
AU  - Satoki Karasawa
AU  - Motoki Azuma
AU  - Takeshi Kasama
AU  - Satoshi Sakamoto
AU  - Yasuaki Kabe
AU  - Takeshi Imai
AU  - Yuki Yamaguchi
AU  - Keisuke Miyazawa
AU  - Hiroshi Handa
TI  - Vitamin K2 Covalently Binds to Bak and Induces Bak-Mediated Apoptosis
AID  - 10.1124/mol.112.082602
DP  - 2012 Dec 10
TA  - Molecular Pharmacology
PG  - mol.112.082602
4099  - http://molpharm.aspetjournals.org/content/early/2012/12/10/mol.112.082602.short
4100  - http://molpharm.aspetjournals.org/content/early/2012/12/10/mol.112.082602.full
AB  - 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 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 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.