Involvement of Akt in mitochondria‐dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog

FEBS Letters

Kang, Seung Koo²  Choi, Kyung Hee¹  Chun, Young Jin²  Kim, Hae Jong²  Mun, Jung Yee²  Kim, Mie Young² 

[1] Department of Biology, College of Natural Sciences, Chung-Ang University, Seoul 156-756, South Korea;Division of Biochemistry, College of Pharmacy, Chung-Ang University, Seoul 156-756, South Korea

关键词: Naphthoquinone analog;    Apoptosis;    Cytochrome c;    Bad;    Akt;    zVAD-fmk;    z-Val-Ala-Asp(OMe)-fluoromethylketone;    DEVD-pNA;    N-acetyl-Asp-Glu-Val-Asp-p-nitroanilide;    IETD-pNA;    N-acetyl-Ile-Glu-Thr-Asp-p-nitroanilide;    LEHD-pNA;    N-acetyl-Leu-Glu-His-Asp-p-nitroanilide;    FITC;    fluorescein isothiocyanate;   

DOI  :  10.1016/S0014-5793(03)01238-9

学科分类：生物化学/生物物理

来源: John Wiley & Sons Ltd.

【 摘 要 】

Vitamin K-related analogs induce growth inhibition via a cell cycle arrest through cdc25A phosphatase inhibition in various cancer cell lines. We report that 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone (DDN), a naphthoquinone analog, induces mitochondria-dependent apoptosis in human promyelocytic leukemia HL-60 cells. DDN induced cytochrome c release, Bax translocation, cleavage of Bid and Bad, and activation of caspase-3, -8, -9 upon the induction of apoptosis. Cleavage of Bid, the caspase-8 substrate, was inhibited by the broad caspase inhibitor z-Val-Ala-Asp(OMe)-fluoromethylketone (zVAD-fmk), whereas cytochrome c release was not affected, suggesting that activation of caspase-8 and subsequent Bid cleavage occur downstream of cytochrome c release. DDN inhibited the activation of Akt detected by decreasing level of phosphorylation. Overexpression of constitutively active Akt protected cells from DDN-induced apoptosis, while dominant negative Akt moderately enhanced cell death. Furthermore, Akt prevented release of cytochrome c and cleavage of Bad in DDN-treated HL-60 cells. Taken together, DDN-induced apoptosis is associated with mitochondrial signaling which involves cytochrome c release via a mechanism inhibited by Akt.

【 授权许可】

Unknown