Differential involvement of Bax and Bak in TRAIL-mediated apoptosis of leukemic T cells

被引:30
作者
Han, J
Goldstein, LA
Gastman, B
Rabinovitz, A
Wang, GQ
Fang, B
Rabinowich, H
机构
[1] Univ Pittsburgh, Inst Canc, Hillman Canc Ctr, Pittsburgh, PA 15213 USA
[2] Univ Texas, MD Anderson Canc Ctr, Univ Pittsburgh Sch Med, Dept Pathol, Houston, TX 77030 USA
[3] Univ Texas, MD Anderson Canc Ctr, Univ Pittsburgh Sch Med, Dept Plast Surg, Houston, TX 77030 USA
[4] Univ Texas, MD Anderson Canc Ctr, Dept Thorac & Cardiovasc Surg, Houston, TX 77030 USA
关键词
apoptosis; Bax; Bak; cytochrome c; mitochondria; leukemia; TRAIL;
D O I
10.1038/sj.leu.2403496
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
TRAIL-induced apoptosis has been considered a promising therapeutic approach for tumors that are resistant to chemotherapy, which is usually mediated via mitochondrial apoptotic cascades. Recent studies have shown that in certain cancer cells, TRAIL-mediated apoptosis is also dependent on mitochondrial involvement, suggesting that similar mechanisms of resistance to chemotherapy might be implicated in the resistance of tumor cells to TRAIL. We have used TRAIL-resistant leukemic cells that are deficient in both Bax and Bak to determine the roles of these Bcl-2 members in TRAIL-mediated apoptosis. Exposure of these cells to TRAIL did not have an impact on cell viability, although it induced the processing of caspase-3 to its active p20 subunit. The activity of the p20 caspase-3 appeared to be inhibited as no autoprocessing of this p20 subunit or cleavage of known caspase-3 substrates were detected. Also, in the absence of Bax and Bak, no release of mitochondrial apoptogenic proteins was observed following TRAIL treatment. Adenoviral transduction of the Bax, but not the Bak gene, to the Bax/Bak-deficient leukemic cells rendered them TRAIL-sensitive as assessed by enhanced apoptotic death and caspase-3 processing. These findings demonstrate preferential utilization of Bax over Bak in leukemic cell response to specific apoptotic stimulation.
引用
收藏
页码:1671 / 1680
页数:10
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