Acetoxycycloheximide (E-73) rapidly induces apoptosis mediated by the release of cytochrome c via activation of c-Jun N-terminal kinase.

Abstract

Cycloheximide (CHX) is an inhibitor of protein synthesis and commonly used to modulate death receptor-mediated apoptosis or to induce apoptosis in a number of normal and transformed cells. In this study we show that a close structural derivative of CHX, acetoxycycloheximide (E-73) induced rapid processing of procaspases and subsequent apoptosis with much higher efficacy than CHX in human leukemia Jurkat T cells. E-73 induced the release of cytochrome c from mitochondria even in the presence of the caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethyl ketone. The Bcl-2 family protein Bcl-x(L) suppressed cytochrome c release as well as processing of procaspases-3, -8, and -9 in E-73-treated cells. In Jurkat T cells transfected with the caspase-8 modulator FLIP(L), E-73 still induced activation of procaspase-3 and subsequent apoptosis, suggesting that the caspase-8 activity is dispensable for apoptosis. In contrast to CHX, E-73 drastically induced activation of extracellular signal-regulated kinase, c-Jun N-terminal kinase (JNK), and p38 MAP kinase. Inhibitory profiles of small-molecular kinase inhibitors revealed that JNK activation was critical for induction of cytochrome c release in E-73-induced apoptosis. Thus, our present results demonstrate that E-73, unlike CHX, induces strong activation of the JNK pathway and triggers rapid apoptosis mediated by the release of cytochrome c.

• Authors: Kimiko Kadohara, Yoshinori Tsukumo, Hikaru Sugimoto, Masayuki Igarashi, Kazuo Nagai, Takao Kataoka
• Journal: Biochemical pharmacology (Biochem Pharmacol) Vol. 69 Issue 4 Pg. 551-60 (Feb 15 2005) ISSN: 0006-2952 [Print] England
• PMID: 15670574 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BCL2L1 protein, human
• CASP8 and FADD-Like Apoptosis Regulating Protein
• CFLAR protein, human
• Intracellular Signaling Peptides and Proteins
• Proto-Oncogene Proteins c-bcl-2
• bcl-X Protein
• Cyclophosphamide
• Cytochromes c
• Cycloheximide
• JNK Mitogen-Activated Protein Kinases
• Caspases
• acetoxycycloheximide

Topics

• Apoptosis (drug effects)
• CASP8 and FADD-Like Apoptosis Regulating Protein
• Caspases (physiology)
• Cell Nucleus (drug effects)
• Cycloheximide (analogs & derivatives, pharmacology)
• Cyclophosphamide (pharmacology)
• Cytochromes c (metabolism)
• DNA Fragmentation (drug effects)
• Enzyme Activation (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (physiology)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Jurkat Cells
• Phosphorylation
• Proto-Oncogene Proteins c-bcl-2 (physiology)
• bcl-X Protein