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Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction
Department of Internal Medicine I, Eberhard-Karls-University, Tübingen, Germany. .
Department of Internal Medicine I, Eberhard-Karls-University, Tübingen, Germany.
Department of Internal Medicine I, Eberhard-Karls-University, Tübingen, Germany.
Department of Internal Medicine I, Eberhard-Karls-University, Tübingen, Germany.ORCID iD: 0000-0001-9518-1411
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1999 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 93, no 9, 3053-3063 p.Article in journal (Refereed) Published
Abstract [en]

Proteases of the caspase family are the critical executioners of apoptosis. Their activation has been mainly studied upon triggering of death receptors, such as CD95 (Fas/APO-1) and tumor necrosis factor-R1, which recruit caspase-8/FLICE as the most proximal effector to the receptor complex. Because apoptosis induced by anticancer drugs has been proposed to involve CD95/CD95 ligand interaction, we investigated the mechanism of caspase activation by daunorubicin, doxorubicin, etoposide, and mitomycin C. In Jurkat leukemic T cells, all drugs induced apoptosis and the cleavage of procaspase-8 to its active p18 subunit. However, cells resistant to CD95 were equally susceptible to anticancer drugs and activated caspase-8 with a similar kinetic and dose response as CD95-sensitive cells. The broad caspase inhibitor benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone prevented apoptosis and caspase-8 activation in response to CD95 and drug treatment, whereas a neutralizing CD95 decoy as well as a dominant-negative FADD construct selectively abrogated CD95, but not drug-induced effects. A potent activation of caspase-8 was also induced by cycloheximide, indicating that it was independent of protein synthesis. Our data, therefore, show that (1) anticancer drug-induced apoptosis does not require de novo synthesis of death ligands or CD95 interaction, and (2) that caspase-8 can be activated in the absence of a death receptor signaling. (C) 1999 by The American Society of Hematology.

Place, publisher, year, edition, pages
American Society of Hematology , 1999. Vol. 93, no 9, 3053-3063 p.
Keyword [en]
cancer-chemotherapy, cell-death, chemotherapy-induced apoptosis, confer immune privilege, cytochrome-c, domain-containing receptor, fadd-dependent apoptosis, nf-kappa-b, poly(adp-ribose) polymerase, signaling complex disc
National Category
Biochemistry and Molecular Biology
URN: urn:nbn:se:liu:diva-87028ISI: 000079984800035PubMedID: 10216102OAI: diva2:584263
Available from: 2013-01-08 Created: 2013-01-08 Last updated: 2013-09-03

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Los, Marek Jan
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