Ying Shao Xu, Seal Sudeshna, Abbassi Nissa, Hockenbery David M, Kiem Hans-Peter, Li Xiao, Pagel John M, Gopal Ajay K, Deeg H J
Shanghai Sixth Hospital, Shanghai Jiaotong University, Shanghai, China.
Leuk Lymphoma. 2007 May;48(5):1003-14. doi: 10.1080/10428190701242358.
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 FLIP(Long) and activated caspase-8, thereby allowing for TRAIL-triggered apoptosis. Overexpression of FLIP(Long) 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.
肿瘤坏死因子相关凋亡诱导配体（TRAIL）优先诱导肿瘤细胞发生程序性细胞死亡（凋亡）。然而，并非所有癌细胞都对TRAIL敏感。我们确定视黄酸受体RXR的激活是否会使细胞对TRAIL介导的凋亡敏感。用RXR特异性视黄酸贝沙罗汀、TRAIL或两者处理白血病细胞系KG1a（抗凋亡）和ML-1（凋亡敏感），并检测凋亡情况。在KG1a细胞中，贝沙罗汀下调FLIP（长型）并激活半胱天冬酶-8，从而引发TRAIL诱导的凋亡。在ML-1细胞中过表达FLIP（长型）可消除凋亡。在未修饰的ML-1细胞中，贝沙罗汀通过截断Bid和释放细胞色素C增强程序性细胞死亡。半胱天冬酶-8的阻断可防止两种细胞系的增强作用；半胱天冬酶-9的阻断仅在ML-1细胞中有显著作用。因此，贝沙罗汀对TRAIL介导的程序性细胞死亡的影响涉及外源性途径的近端事件；然而，下游信号在ML-1细胞中涉及内源性途径，而在KG1a细胞中则不然。这些研究为白血病细胞程序性细胞死亡的调控增加了更多信息，在设计治疗策略时必须予以考虑。
