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Involvement of Akt in mitochondria‐dependent apoptosis induced by a cdc25 phosphatase inhibitor naphthoquinone analog
Author(s) -
Kim Hae Jong,
Kang Seung Koo,
Mun Jung Yee,
Chun Young Jin,
Choi Kyung Hee,
Kim Mie Young
Publication year - 2003
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/s0014-5793(03)01238-9
Subject(s) - protein kinase b , cytochrome c , apoptosis , microbiology and biotechnology , mitochondrion , caspase , chemistry , biology , programmed cell death , cancer research , biochemistry
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.