ABSTRACT The marine alkaloid ascididemin (ASC) was shown to exert cytotoxicity even against multidrug-resistant cancer cells. Here, we address the signaling pathways utilized by ASC to

trigger apoptosis in Jurkat leukemia T cells. We show that ASC (0.5–20 _μ_ M) induces a mitochondrial pathway that requires the activation of the initiator caspase-2 upstream of

mitochondria. ASC-triggered apoptosis occurred independent of CD95, but required mitochondrial dysfunction. The activation of caspase-2 was shown to precede the processing of caspase-8, -9

and -3. The specific caspase-2 inhibitor zVDVADfmk abrogated ASC-induced DNA fragmentation almost completely. Overexpression of Bcl-xL blocked caspase-8 but not caspase-2 processing.

release and DNA fragmentation indicating that JNK contributes to, but is not necessary for ASC-mediated apoptosis. Thus, ASC triggers a pathway in which early activation of caspase-2

provides a possible link between its DNA-damaging activity and the induction of mitochondrial dysfunction. The activation of JNK contributes to this signaling upstream of mitochondria.

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support SIMILAR CONTENT BEING VIEWED BY OTHERS CASPASE-2 IS A MEDIATOR OF APOPTOTIC SIGNALING IN RESPONSE TO GEMTUZUMAB OZOGAMICIN IN ACUTE MYELOID LEUKEMIA Article Open access 11 June 2022

NOVEL MERIOLIN DERIVATIVES ACTIVATE THE MITOCHONDRIAL APOPTOSIS PATHWAY IN THE PRESENCE OF ANTIAPOPTOTIC BCL-2 Article Open access 09 March 2024 PHARMACOLOGICAL TARGETING OF

CASPASE-8/C-FLIPL HETERODIMER ENHANCES COMPLEX II ASSEMBLY AND ELIMINATION OF PANCREATIC CANCER CELLS Article Open access 03 January 2025 REFERENCES * Antlsperger DSM, Dirsch VM, Ferreira D,

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ACKNOWLEDGEMENTS We thank Drs Peter H Krammer and Henning Walczak (German Cancer Research Center, Heidelberg, Germany) as well as Dr Schulze-Osthoff (University of Münster, Germany) for

supplying Jurkat T cell clones, and Dr X Wang (University of Texas, Dallas, USA) for providing the anti-Bid antibody. We gratefully acknowledge the excellent lab work of Katharina von

Gersdorff. AUTHOR INFORMATION AUTHORS AND AFFILIATIONS * Department of Pharmacy, Center of Drug Research, University of Munich, Butenandtstraße 5-13, Munich, D-81377, Germany Verena M

Dirsch, Stephanie O Kirschke & Angelika M Vollmar * Department of Chemistry, University of Munich, Munich, D-81377, Germany Michael Estermeier & Bert Steffan Authors * Verena M

Dirsch View author publications You can also search for this author inPubMed Google Scholar * Stephanie O Kirschke View author publications You can also search for this author inPubMed 

Google Scholar * Michael Estermeier View author publications You can also search for this author inPubMed Google Scholar * Bert Steffan View author publications You can also search for this

author inPubMed Google Scholar * Angelika M Vollmar View author publications You can also search for this author inPubMed Google Scholar CORRESPONDING AUTHOR Correspondence to Verena M

Dirsch. ADDITIONAL INFORMATION This work was supported by the Deutsche Forschungsgemeinschaft (SFB 369) RIGHTS AND PERMISSIONS Reprints and permissions ABOUT THIS ARTICLE CITE THIS ARTICLE

Dirsch, V., Kirschke, S., Estermeier, M. _et al._ Apoptosis signaling triggered by the marine alkaloid ascididemin is routed via caspase-2 and JNK to mitochondria. _Oncogene_ 23, 1586–1593

(2004). https://doi.org/10.1038/sj.onc.1207281 Download citation * Received: 07 February 2003 * Revised: 29 September 2003 * Accepted: 14 October 2003 * Published: 29 December 2003 * Issue

Date: 26 February 2004 * DOI: https://doi.org/10.1038/sj.onc.1207281 SHARE THIS ARTICLE Anyone you share the following link with will be able to read this content: Get shareable link Sorry,

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caspase-2 * mitochondria