期刊
LEUKEMIA & LYMPHOMA
卷 48, 期 5, 页码 1003-1014出版社
TAYLOR & FRANCIS LTD
DOI: 10.1080/10428190701242358
关键词
TRAIL; bexarotene; apoptosis; resistance; intrinsic and extrinsic pathways
资金
- NATIONAL CANCER INSTITUTE [R21CA119599] Funding Source: NIH RePORTER
- NATIONAL HEART, LUNG, AND BLOOD INSTITUTE [R01HL082941, P01HL036444] Funding Source: NIH RePORTER
- NCI NIH HHS [CA119599] Funding Source: Medline
- NHLBI NIH HHS [HL082941, HL36444] Funding Source: Medline
Tumor necrosis factor-related apoptosis-inducing ligand ( TRAIL) induces programmed cell death ( apoptosis) preferentially in tumor cells. However, not all cancer cells are sensitive to TRAIL. We determined whether ligation of the retinoid receptor, RXR, would sensitize cells to TRAIL-mediated apoptosis. The leukemic cell lines KG1a ( apoptosis-resistant) and ML-1 ( apoptosis-sensitive) were treated with the RXR-specific retinoid bexarotene, TRAIL, or both, and apoptosis was determined. In KG1a cells, bexarotene downregulated FLIPLong and activated caspase-8, thereby allowing for TRAIL-triggered apoptosis. Overexpression of FLIPLong in ML-1 cells abrogated apoptosis. In unmodified ML-1 cells bexarotene enhanced programmed cell death via truncation of Bid and release of cytochrome C. Blockade of caspase-8 prevented enhancement in both cell lines; blockade of caspase-9 had a significant effect only in ML-1 cells. Thus, the effect of bexarotene on TRAIL-mediated programmed cell death involved proximal events of the extrinsic pathway; however, downstream signals involved the intrinsic pathway in ML-1 but not in KG1a cells. These studies add further information to the regulation of programmed cell death in leukemic cells that have to be considered when designing therapeutic strategies.
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