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

Abstract

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.

• Authors: Hae Jong Kim, Seung Koo Kang, Jung Yee Mun, Young Jin Chun, Kyung Hee Choi, Mie Young Kim
• Journal: FEBS letters (FEBS Lett) Vol. 555 Issue 2 Pg. 217-22 (Dec 04 2003) ISSN: 0014-5793 [Print] England
• PMID: 14644418 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 2,3-dichloro-5,8-dihydroxy-1,4-naphthoquinone
• Amino Acid Chloromethyl Ketones
• BAD protein, human
• BAX protein, human
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• Carrier Proteins
• Caspase Inhibitors
• Enzyme Inhibitors
• Naphthoquinones
• Proto-Oncogene Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-2-Associated X Protein
• bcl-Associated Death Protein
• benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
• Cytochromes c
• AKT1 protein, human
• Protein Serine-Threonine Kinases
• Proto-Oncogene Proteins c-akt
• cdc25 Phosphatases
• Caspases

Topics

• Amino Acid Chloromethyl Ketones (pharmacology)
• Apoptosis (drug effects, physiology)
• BH3 Interacting Domain Death Agonist Protein
• Carrier Proteins (metabolism)
• Caspase Inhibitors
• Caspases (metabolism)
• Cytochromes c (metabolism)
• Enzyme Activation (drug effects)
• Enzyme Inhibitors (pharmacology)
• HL-60 Cells
• Humans
• Immunoblotting
• Mitochondria (metabolism)
• Naphthoquinones (antagonists & inhibitors, pharmacology)
• Protein Serine-Threonine Kinases (metabolism, pharmacology)
• Proto-Oncogene Proteins (metabolism, pharmacology)
• Proto-Oncogene Proteins c-akt
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction
• bcl-2-Associated X Protein
• bcl-Associated Death Protein
• cdc25 Phosphatases (antagonists & inhibitors)