Actinomycin D-mediated sensitization of AIDS-Kaposi's sarcoma cells to Fas-mediated apoptosis: involvement of the mitochondrion-dependent pathway.

Abstract

Fas engagement rapidly induces formation of the death-inducing signaling complex (DISC) that consists of Fas, FADD and pro-caspase-8. Activated caspase-8 at the DISC directly activates downstream caspases, resulting in induction of apoptosis of the independent mitochondria. In this study, we have obtained evidence demonstrating that Fas-mediated apoptosis in AIDS-KS cells takes place in a mitochondria-dependent manner. FADD and pro-caspase-8 were detected in immunoprecipitates with anti-Fas antibody in anti-Fas mAb (CH-11)-treated Hut 78, a typical Fas-sensitive cell line. On the other hand, DISC formation by CH-11 was markedly reduced in AIDS-KS cells. In addition, CH-11-induced activation of caspase-8-like protease in AIDS-KS cells was much less pronounced compared with that in Hut 78; however, a caspase-8 inhibitor, zIETD-fmk, completely blocked the apoptosis. Further, a caspase-9 inhibitor, zLEHD-fmk, markedly inhibited Fas-mediated apoptosis in AIDS-KS cells. Several apoptotic stimuli induce mitochondria activation allowing cytochrome c release from the mitochondria. In the apoptosome, cytochrome c and Apaf-1 activate caspase-9 which subsequently leads to the activation of caspase-3. In AIDS-KS cells, CH-11 triggered cytochrome c release, an event which was inhibited by zIETD-fmk. Further, a caspase-3 inhibitor, zDEVD-fmk completely inhibited the apoptosis. Altogether, the present data provide evidence that the Fas signal in AIDS-KS cells is preferentially transduced through the mitochondria-dependent pathway, which is initiated by caspase-8 activation.

• Authors: Shunsuke Mori, Kaoru Murakami-Mori, Shuji Nakamura, Benjamin Bonavida
• Journal: International journal of oncology (Int J Oncol) Vol. 20 Issue 4 Pg. 819-26 (Apr 2002) ISSN: 1019-6439 [Print] Greece
• PMID: 11894131 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Adaptor Proteins, Signal Transducing
• Carrier Proteins
• Cytochrome c Group
• Enzyme Inhibitors
• FADD protein, human
• Fas-Associated Death Domain Protein
• fas Receptor
• Dactinomycin
• CASP8 protein, human
• CASP9 protein, human
• Caspase 8
• Caspase 9
• Caspases

Topics

• Acquired Immunodeficiency Syndrome (metabolism, pathology)
• Adaptor Proteins, Signal Transducing
• Apoptosis
• Blotting, Western
• Carrier Proteins (metabolism)
• Caspase 8
• Caspase 9
• Caspases (metabolism)
• Cell Survival (drug effects)
• Cytochrome c Group (metabolism)
• Dactinomycin (pharmacology)
• Enzyme Activation
• Enzyme Inhibitors (pharmacology)
• Fas-Associated Death Domain Protein
• Humans
• Mitochondria (metabolism)
• Sarcoma, Kaposi (metabolism, pathology)
• Signal Transduction (physiology)
• Tumor Cells, Cultured (drug effects, metabolism)
• fas Receptor (physiology)