Anticancer drugs induce caspase-8/FLICE activation and apoptosis in the absence of CD95 receptor/ligand interaction
1999 (English)In: Blood, ISSN 0006-4971, E-ISSN 1528-0020, Vol. 93, no 9, 3053-3063 p.Article in journal (Refereed) Published
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.
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
Biochemistry and Molecular Biology
IdentifiersURN: urn:nbn:se:liu:diva-87028ISI: 000079984800035PubMedID: 10216102OAI: oai:DiVA.org:liu-87028DiVA: diva2:584263