Activation of caspase-8 in 3-deazaadenosine-induced apoptosis of U-937 cells occurs downstream of caspase-3 and caspase-9 without Fas receptor-ligand interaction.
- Author:
Yeo Jin CHAE
1
;
Ho Shik KIM
;
Hyang Shuk RHIM
;
Bo Eun KIM
;
Seong Whan JEONG
;
In Kyung KIM
Author Information
1. Department of Biochemistry, College of Medicine, The Catholic University of Korea, Seoul, Korea.
- Publication Type:Original Article ; Research Support, Non-U.S. Gov't
- Keywords:
3-deazaadenosine;
caspase;
caspase inhibitor;
apoptosis
- MeSH:
Amino Acid Chloromethyl Ketones/pharmacology;
Apoptosis/*drug effects;
Bongkrekic Acid/pharmacology;
Caspases/*metabolism;
Cell Line;
Cyclosporine/pharmacology;
Cytochrome c/drug effects/metabolism;
Enzyme Activation;
Human;
Leukocytes, Mononuclear/cytology;
Ligands;
Membrane Glycoproteins/metabolism;
Tubercidin/*pharmacology;
U937 Cells
- From:Experimental & Molecular Medicine
2001;33(4):284-292
- CountryRepublic of Korea
- Language:English
-
Abstract:
3-Deazaadenosine (DZA), a cellular methylation blocker was reported to induce the caspase-3-like activities-dependent apoptosis in U-937 cells. In this study, we analyzed the activation pathway of the caspase cascade involved in the DZA-induced apoptosis using specific inhibitors of caspases. In the U-937 cells treated with DZA, cytochrome c release from mitochondria and subsequent activation of caspase-9, -8 and -3 were observed before the induction of apoptosis. zDEVD-Fmk, a specific inhibitor of caspase-3, and zLEHD-Fmk, a specific inhibitor of caspase-9, prevented the activation of caspase-8 but neither caspase-3 nor caspase-9, indicating that caspase-8 is downstream of both caspase-3 and caspase-9, which are activated by independent pathways. zVAD-Fmk, a universal inhibitor of caspases, kept the caspase-3 from being activated but not caspase-9. Moreover, ZB4, an antagonistic Fas-antibody, exerted no effect on the activation of caspase-8 and induction of apoptosis by DZA. In addition, zVAD-Fmk and mitochondrial permeability transition pore (MPTP) inhibitors such as cyclosporin A (CsA) and bongkrekic acid (BA) did not block the release of cytochrome c from mitochondria. Taken together, these results suggest that in the DZA-induced apoptosis, caspase-8 may serve as an executioner caspase and be activated downstream of both caspase-3 and caspase-9, independently of Fas receptor-ligand interaction. And caspase-3 seems to be activated by other caspses including IETDase-like enzyme and caspse-9 seems to be activated by cytochrome c released from mitochondria without the involvement of caspases and CsA- and BA- inhibitory MPTP.
