Irciniastatin A induces JNK activation that is involved in caspase-8-dependent apoptosis via the mitochondrial pathway.

Abstract

Irciniastatin A (ISA)/psymberin, a pederin-type natural product isolated from marine sponge, exhibits extremely potent and selective cytotoxicity against certain human cancer cell lines, but its molecular target and cytotoxic mechanisms are still unknown. Here we show that ISA is a potent inhibitor of protein translation, and induces apoptosis accompanied with activation of the stress-activated protein kinases via the mitochondrial pathway in human leukemia Jurkat cells. ISA potently inhibited protein translation, and induced a slow but prolonged activation of the stress-activated protein kinases, JNK and p38, at between 1h and 6h after treatment. In Bcl-x(L)-transfected cells, the activation of JNK and p38 by ISA was shortened. The same results were obtained in the cells treated with N-acetyl-L-cysteine, suggesting that the prolonged activation of JNK and p38 by ISA is mediated by reactive oxygen species generated from mitochondria. ISA strongly induced apoptosis, which was partially suppressed by the JNK inhibitor SP600125, but not by the p38 inhibitor SB202190. Apoptosis induction by ISA was partially reduced, but not suppressed by SP600125 in caspase-8-deficient Jurkat cells. These results suggest that ISA activates stress-activated kinases by a mitochondria-mediated mechanism, and that activation of JNK is required for caspase-8-dependent apoptosis.

• Authors: Takumi Chinen, Yoko Nagumo, Tsubasa Watanabe, Takamichi Imaizumi, Masatoshi Shibuya, Takao Kataoka, Naoki Kanoh, Yoshiharu Iwabuchi, Takeo Usui
• Journal: Toxicology letters (Toxicol Lett) Vol. 199 Issue 3 Pg. 341-6 (Dec 15 2010) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 20920557 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2010 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Antineoplastic Agents
• Coumarins
• Protein Synthesis Inhibitors
• Pyrones
• Reactive Oxygen Species
• psymberin
• JNK Mitogen-Activated Protein Kinases
• p38 Mitogen-Activated Protein Kinases
• Caspase 8

Topics

• Antineoplastic Agents (pharmacology)
• Apoptosis (drug effects)
• Caspase 8 (physiology)
• Coumarins
• Enzyme Activation (drug effects)
• Humans
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Jurkat Cells
• Mitochondria (drug effects, physiology)
• Phosphorylation
• Protein Biosynthesis (drug effects)
• Protein Synthesis Inhibitors (pharmacology)
• Pyrones (pharmacology)
• Reactive Oxygen Species (metabolism)
• p38 Mitogen-Activated Protein Kinases (metabolism)