Cuello M, Coats A O, Darko I, Ettenberg S A, Gardner G J, Nau M M, Liu J R, Birrer M J, Lipkowitz S
Laboratory of Cellular and Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892-4255, USA.
Cell Death Differ. 2004 May;11(5):527-41. doi: 10.1038/sj.cdd.4401387.
The majority of ovarian cancer cells are resistant to apoptosis induced by tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). Subtoxic concentrations of the semisynthetic retinoid N-(4-hydroxyphenyl)retinamide (4HPR) enhanced TRAIL-mediated apoptosis in ovarian cancer cell lines but not in immortalized nontumorigenic ovarian epithelial cells. The enhancement of TRAIL-mediated apoptosis by 4HPR was not due to changes in the levels of proteins known to modulate TRAIL sensitivity. The combination of 4HPR and TRAIL enhanced cleavage of multiple caspases in the death receptor pathway (including the two initiator caspases, caspase-8 and caspase-9). The 4HPR and TRAIL combination leads to mitochondrial permeability transition, significant increase in cytochrome c release, and increased caspase-9 activation. Caspase-9 may further activate caspase-8, generating an amplification loop. Stable overexpression of Bcl-xL abrogates the interaction between 4HPR and TRAIL at the mitochondrial level by blocking cytochrome c release. As a consequence, a decrease in activation of caspase-9, caspase-8, and TRAIL-mediated apoptosis occurs. These results indicate that the enhancement in TRAIL-mediated apoptosis induced by 4HPR is due to the increase in activation of multiple caspases involving an amplification loop via the mitochondrial-death pathway. These findings offer a promising and novel strategy for the treatment of ovarian cancer.
大多数卵巢癌细胞对肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导的凋亡具有抗性。半合成维甲酸N-(4-羟基苯基)视黄酸酰胺（4HPR）的亚毒性浓度增强了TRAIL介导的卵巢癌细胞系凋亡，但对永生化的非致瘤性卵巢上皮细胞无此作用。4HPR增强TRAIL介导的凋亡并非由于已知调节TRAIL敏感性的蛋白质水平发生变化。4HPR与TRAIL的联合作用增强了死亡受体途径中多种半胱天冬酶的切割（包括两种起始半胱天冬酶，半胱天冬酶-8和半胱天冬酶-9）。4HPR与TRAIL的联合作用导致线粒体通透性转换、细胞色素c释放显著增加以及半胱天冬酶-9激活增加。半胱天冬酶-9可能进一步激活半胱天冬酶-8，形成一个放大环。Bcl-xL的稳定过表达通过阻断细胞色素c释放，在线粒体水平消除了4HPR与TRAIL之间的相互作用。结果，半胱天冬酶-9、半胱天冬酶-8的激活以及TRAIL介导的凋亡均减少。这些结果表明，4HPR诱导的TRAIL介导的凋亡增强是由于通过线粒体死亡途径涉及放大环的多种半胱天冬酶激活增加所致。这些发现为卵巢癌的治疗提供了一种有前景的新策略。
