Cephalostatin 1 Selectively Triggers the Release of Smac/DIABLO and Subsequent Apoptosis That Is Characterized by an Increased Density of the Mitochondrial Matrix

Verena M. Dirsch, Irina M. Müller, Sören T. Eichhorst, George Pettit, Yoshiaki Kamano, Masuo Inoue, Jun-Ping Xu, Yoshitatsu Ichihara, Gerhard Wanner, Angelika M. Vollmar

Research output: Contribution to journalArticle

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Abstract

Cephalostatin 1 is a bis-steroidal marine natural product with a unique cytotoxicity profile in the in vitro screen system of the National Cancer Institute, suggesting that it may affect novel molecular target(s). Here we show that cephalostatin 1 induces a novel pathway of receptor-independent apoptosis that selectively uses Smac/DIABLO (second mitochondria-derived activator of caspases/direct inhibitor of apoptosis-binding protein with a low isoelectric point) as a mitochondrial signaling molecule. At nanomolar concentrations, cephalostatin 1 triggers dose- and time-dependent DNA fragmentation in leukemia Jurkat T cells. Apoptosis was found to be dependent on caspase activity because the pan-caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp(OMe)-fluoromethylketone blocks cephalostatin 1-mediated DNA fragmentation. The CD95 death receptor as well as other caspase-8-requiring death receptors were not involved because Jurkat T cells lacking the CD95 receptor or caspase-8 and control cells responded equally to cephalostatin 1. Although cephalostatin 1 affects mitochondria by dissipating the mitochondrial membrane potential, neither cytochrome c nor apoptosis-inducing factor is released, as shown by Western blot analysis. Interestingly, cephalostatin 1 selectively triggers the mitochondrial release of the inhibitor of apoptosis antagonist Smac/DIABLO. Overexpression of the antiapoptotic protein Bcl-xL delayed both Smac/DIABLO release and onset of apoptosis, suggesting that Smac/DIABLO is required for cephalostatin 1-induced apoptosis. This new mitochondrial pathway is accompanied by marked structural changes of mitochondria as shown by transmission electron microscopy.

Original languageEnglish (US)
Pages (from-to)8869-8876
Number of pages8
JournalCancer Research
Volume63
Issue number24
StatePublished - Dec 15 2003

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Inhibitor of Apoptosis Proteins
Caspase Inhibitors
Isoelectric Point
Carrier Proteins
Mitochondria
Apoptosis
Death Domain Receptors
Jurkat Cells
Caspase 8
DNA Fragmentation
Apoptosis Inducing Factor
National Cancer Institute (U.S.)
cephalostatin I
Mitochondrial Membrane Potential
Caspases
Cytochromes c
Biological Products
Transmission Electron Microscopy
Leukemia
Western Blotting

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

Cite this

Cephalostatin 1 Selectively Triggers the Release of Smac/DIABLO and Subsequent Apoptosis That Is Characterized by an Increased Density of the Mitochondrial Matrix. / Dirsch, Verena M.; Müller, Irina M.; Eichhorst, Sören T.; Pettit, George; Kamano, Yoshiaki; Inoue, Masuo; Xu, Jun-Ping; Ichihara, Yoshitatsu; Wanner, Gerhard; Vollmar, Angelika M.

In: Cancer Research, Vol. 63, No. 24, 15.12.2003, p. 8869-8876.

Research output: Contribution to journalArticle

Dirsch, VM, Müller, IM, Eichhorst, ST, Pettit, G, Kamano, Y, Inoue, M, Xu, J-P, Ichihara, Y, Wanner, G & Vollmar, AM 2003, 'Cephalostatin 1 Selectively Triggers the Release of Smac/DIABLO and Subsequent Apoptosis That Is Characterized by an Increased Density of the Mitochondrial Matrix', Cancer Research, vol. 63, no. 24, pp. 8869-8876.
Dirsch, Verena M. ; Müller, Irina M. ; Eichhorst, Sören T. ; Pettit, George ; Kamano, Yoshiaki ; Inoue, Masuo ; Xu, Jun-Ping ; Ichihara, Yoshitatsu ; Wanner, Gerhard ; Vollmar, Angelika M. / Cephalostatin 1 Selectively Triggers the Release of Smac/DIABLO and Subsequent Apoptosis That Is Characterized by an Increased Density of the Mitochondrial Matrix. In: Cancer Research. 2003 ; Vol. 63, No. 24. pp. 8869-8876.
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