Role of Smac in cephalostatin-induced cell death

A. Rudy, N. López-Antón, N. Barth, George Pettit, V. M. Dirsch, K. Schulze-Osthoff, M. Rehm, J. H M Prehn, M. Vogler, S. Fulda, A. M. Vollmar

Research output: Contribution to journalArticlepeer-review

19 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1930-1940
Number of pages11
JournalCell Death and Differentiation
Issue number12
StatePublished - 2008

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology


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