Role of Smac in cephalostatin-induced cell death.

Abstract

Cephalostatin 1 is a natural compound isolated from a marine worm that induces apoptosis in tumor cells via an apoptosome-independent but caspase-9-dependent pathway and through an endoplasmic reticulum stress response that is accompanied by caspase-4 activation. Here, we show that cephalostatin evokes mitochondrial Smac (second mitochondria-derived activator of caspases) but not cytochrome c release in various carcinoma cell lines. We also show that Smac is critically involved in caspase-9 activation as evidenced by gene silencing experiments. Remarkably, caspase-2 appears to be a major target for cephalostatin-induced cytosolic Smac. Using biochemical and genetic inhibition experiments, we demonstrate that caspase-2 participates in the apoptotic machinery induced by cephalostatin. Cephalostatin-activated caspase-2 appears to act as initiator caspase and is not involved in the activation of caspase-9. Importantly, experiments immunoprecipitating PIDD (p53-induced protein with a DD), RAIDD (RIP-associated ICH-1/CED-3-homologous protein with DD) and caspase-2 identify cephalostatin as an experimental drug that induces the formation of the PIDDosome. The bis-steroid cephalostatin proves to be both a helpful tool to investigate apoptotic signaling and a promising chemotherapeutic agent.

• Authors: A Rudy, N López-Antón, N Barth, G R Pettit, V M Dirsch, K Schulze-Osthoff, M Rehm, J H M Prehn, M Vogler, S Fulda, A M Vollmar
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 15 Issue 12 Pg. 1930-40 (Dec 2008) ISSN: 1476-5403 [Electronic] England
• PMID: 18806754 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Apoptosis Regulatory Proteins
• Carrier Proteins
• DIABLO protein, human
• Death Domain Receptor Signaling Adaptor Proteins
• Intracellular Signaling Peptides and Proteins
• Mitochondrial Proteins
• PIDD1 protein, human
• Phenazines
• Proto-Oncogene Proteins c-bcl-2
• Spiro Compounds
• Steroids
• cephalostatin I
• Cytochromes c
• JNK Mitogen-Activated Protein Kinases
• Calpain
• Caspase 2
• Caspase 9

Topics

• Apoptosis Regulatory Proteins
• Calpain (metabolism)
• Carrier Proteins (metabolism)
• Caspase 2 (metabolism)
• Caspase 9 (metabolism)
• Cell Death (drug effects)
• Cytochromes c (metabolism)
• Death Domain Receptor Signaling Adaptor Proteins
• Enzyme Activation (drug effects)
• Gene Silencing (drug effects)
• Humans
• Intracellular Signaling Peptides and Proteins (metabolism)
• JNK Mitogen-Activated Protein Kinases (metabolism)
• Jurkat Cells
• Mitochondrial Proteins (metabolism)
• Phenazines (pharmacology)
• Proto-Oncogene Proteins c-bcl-2 (metabolism)
• Signal Transduction (drug effects)
• Spiro Compounds (pharmacology)
• Steroids (pharmacology)