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Two distinct Fas-activated signaling pathways revealed by an antitumor drug D609

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Abstract

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.

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Acknowledgements

We thank Drs K Sakamaki and S Yonehara for kindly providing caspase-8-deficient MEFs. This study was supported in part by a grant for Scientific Research on Priority Areas, a grant for Center of Excellence Research, a grant for the 21st century COE program, and a grant for Scientific Research from the Ministry of Education, Science, Sports, and Culture of Japan.

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  1. Laboratory of Molecular Genetics, Department of Post-Genomics and Diseases, Osaka University Medical School, Solution Oriented Research for Science and Technology (SORST), Japan Science and Technology Corporation, 2-2 Yamadaoka, Suita, Osaka, 565-0871, Japan

    Lilin Zhang, Shigeomi Shimizu & Yoshihide Tsujimoto

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  1. Lilin Zhang
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  2. Shigeomi Shimizu
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  3. Yoshihide Tsujimoto
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Correspondence to Yoshihide Tsujimoto.

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Zhang, L., Shimizu, S. & Tsujimoto, Y. Two distinct Fas-activated signaling pathways revealed by an antitumor drug D609. Oncogene 24, 2954–2962 (2005). https://doi.org/10.1038/sj.onc.1208388

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