Bcl-2 family inhibition sensitizes human prostate cancer cells to docetaxel and promotes unexpected apoptosis under caspase-9 inhibition
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Hiroki Tamaki1,2, Nanae Harashima1, Miho Hiraki3, Naoko Arichi3, Nobuhiro Nishimura2, Hiroaki Shiina3, Kohji Naora2, Mamoru Harada1
1Department of Immunology, Shimane University Faculty of Medicine, Shimane, Japan.
2Department of Pharmacy, Shimane University Hospital, Shimane, Japan.
3Department of Urology, Shimane University Faculty of Medicine, Shimane, Japan.
Mamoru Harada, e-mail: [email protected]
Keywords: prostate cancer, docetaxel, apoptosis, Bcl-2, Bcl-xL
Received: July 26, 2014 Accepted: September 30, 2014 Published: October 15, 2014
Docetaxel (DTX) is a useful chemotherapeutic drug for the treatment of hormone-refractory prostate cancer. However, emergence of DTX resistance has been a therapeutic hurdle. In this study, we investigated the effect of combining DTX with Bcl-2 family inhibitors using human prostate cancer cell lines (PC3, LNCaP, and DU145 cells). PC3 cells were less sensitive to DTX than were the other two cell lines. In contrast to ABT-199, which inhibits Bcl-2 and Bcl-w, both ABT-263 and ABT-737, which inhibit Bcl-2, Bcl-xL, and Bcl-w, significantly augmented the antitumor effect of DTX on PC3 cells. ABT-263 also enhanced the antitumor effect of DTX on a DTX-resistant PC3 variant cell line. The antitumor effect of ABT-263 was due mainly to its inhibitory effect on Bcl-xL. In a xenograft mouse model, DTX and ABT-737 combination therapy significantly inhibited PC3 tumor growth. Interestingly, although ABT-263 activated caspase-9 in PC3 cells, inhibition of caspase-9 unexpectedly promoted ABT-263-induced apoptosis in a caspase-8-dependent manner. This augmented apoptosis was also observed in LNCaP cells. These findings indicate that Bcl-xL inhibition can sensitize DTX-resistant prostate cancer cells to DTX, and they reveal a unique apoptotic pathway in which antagonism of Bcl-2 family members in caspase-9-inhibited prostate cancer cells triggers caspase-8-dependent apoptosis.
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