Two distinct Fas-activated signaling pathways revealed by an antitumor drug D609.
During the process of death receptor-mediated apoptosis, Bid is cleaved by activated caspase-8, and then cleaved Bid conveys apoptotic signals to the mitochondria by activating Bax/Bak. In the present study, we found that D609 (an antitumor drug with multiple activities) blocks Fas-induced apoptosis. D609 did not interfere with activation of caspase-8 and cleavage of Bid, whereas it blocked cytochrome c release from the mitochondria by inhibiting the activation of Bax and Bak. D609 had no protective effect against apoptosis of SKW6.4 cells, which are typical type I cells. Studies using permeabilized cells revealed that in addition to activation of caspase-8, Fas activated a distinct and D609-sensitive signaling pathway that transmitted signal(s) sensitizing the mitochondria to apoptotic stimuli, and that D609 itself promoted mitochondrial resistance to apoptotic stimuli.
Zhang
Lilin
L
Laboratory of Molecular Genetics, Department of Post-Genomics and Diseases, Osaka University Medical School, Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, 2-2 Yamadaoka, Suita, Osaka 565-0871, Japan.
Shimizu
Shigeomi
S
Tsujimoto
Yoshihide
Y
D000970:Antineoplastic Agents / Q000494:pharmacology*; D051023:BH3 Interacting Domain Death Agonist Protein; D001952:Bridged-Ring Compounds / Q000494:pharmacology*; D002352:Carrier Proteins / Q000378:metabolism; D045304:Cytochromes c / Q000378:metabolism; D006367:HeLa Cells; D006801:Humans; D019169:Jurkat Cells; D008565:Membrane Proteins / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects; D009636:Norbornanes; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D018124:Receptors, Tumor Necrosis Factor / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects*; D013859:Thiocarbamates; D013871:Thiones / Q000494:pharmacology*; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor
D000970:Antineoplastic Agents; C494772:BAK1 protein, human; C494826:BAX protein, human; D051023:BH3 Interacting Domain Death Agonist Protein; C494814:BID protein, human; D001952:Bridged-Ring Compounds; D002352:Carrier Proteins; C491901:FAS protein, human; D008565:Membrane Proteins; D009636:Norbornanes; D019253:Proto-Oncogene Proteins c-bcl-2; D018124:Receptors, Tumor Necrosis Factor; D013859:Thiocarbamates; D013871:Thiones; D050998:bcl-2 Homologous Antagonist-Killer Protein; D051028:bcl-2-Associated X Protein; D019014:fas Receptor; C046498:tricyclodecane-9-yl-xanthogenate; D045304:Cytochromes c