Institute for Experimental Cancer Research in Pediatrics, Goethe-University, Frankfurt, Germany.
Cell Death Dis. 2012 Nov 29;3(11):e432. doi: 10.1038/cddis.2012.163.
To search for novel strategies to enhance the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-induced apoptosis pathways in glioblastoma, we used the B-cell lymphoma 2/Bcl2-like 2-inhibitor ABT-737. Here we report that ABT-737 and TRAIL cooperate to induce apoptosis in several glioblastoma cell lines in a highly synergistic manner (combination index <0.1). Interestingly, the concerted action of ABT-737 and TRAIL to trigger the accumulation of truncated Bid (tBid) at mitochondrial membranes is identified as a key underlying mechanism. ABT-737 and TRAIL cooperate to cleave BH3-interacting domain death agonist (Bid) into its active fragment tBid, leading to increased accumulation of tBid at mitochondrial membranes. Coinciding with tBid accumulation, the activation of Bcl2-associated X protein (Bax), loss of mitochondrial membrane potential, release of cytochrome-c and second mitochondria-derived activator of caspase (Smac) into the cytosol and caspase activation are strongly increased in cotreated cells. Of note, knockdown of Bid significantly decreases ABT-737- and TRAIL-mediated Bax activation and apoptosis. Also, caspase-3 silencing reduces ABT-737- and TRAIL-induced Bid cleavage and apoptosis, indicating that a caspase-3-driven, mitochondrial feedback loop contributes to Bid processing. Importantly, ABT-737 profoundly enhances TRAIL-triggered apoptosis in primary cultured glioblastoma cells derived from tumor material, underlining the clinical relevance. Also, ABT-737 acts in concert with TRAIL to suppress tumor growth in an in vivo glioblastoma model. In conclusion, the rational combination of ABT-737 and TRAIL cooperates to trigger tBid mitochondrial accumulation and apoptosis. This approach presents a promising strategy for targeting the apoptosis pathways in glioblastoma, which warrants further investigation.
为了寻找增强胶质母细胞瘤中肿瘤坏死因子相关凋亡诱导配体（TRAIL）诱导凋亡途径的新策略，我们使用了 B 细胞淋巴瘤 2/Bcl2 样 2 抑制剂 ABT-737。在这里，我们报告 ABT-737 和 TRAIL 以高度协同的方式（组合指数<0.1）共同诱导几种胶质母细胞瘤细胞系凋亡。有趣的是，鉴定出 ABT-737 和 TRAIL 协同作用以在线粒体膜上引发截断 Bid（tBid）的积累是一种关键的潜在机制。ABT-737 和 TRAIL 共同作用将 BH3 相互作用结构域死亡激动剂（Bid）切割成其活性片段 tBid，导致 tBid 在线粒体膜上的积累增加。与 tBid 积累同时，Bcl2 相关 X 蛋白（Bax）的激活、线粒体膜电位的丧失、细胞色素 c 和第二线粒体衍生的半胱天冬酶激活物（Smac）释放到细胞质以及半胱天冬酶的激活在共处理的细胞中强烈增加。值得注意的是，Bid 的敲低显著降低了 ABT-737 和 TRAIL 介导的 Bax 激活和凋亡。此外，caspase-3 沉默减少了 ABT-737 和 TRAIL 诱导的 Bid 切割和凋亡，表明 caspase-3 驱动的线粒体反馈环有助于 Bid 加工。重要的是，ABT-737 可在源自肿瘤材料的原代培养胶质母细胞瘤细胞中显著增强 TRAIL 触发的凋亡，强调了其临床相关性。此外，ABT-737 与 TRAIL 协同作用以抑制体内胶质母细胞瘤模型中的肿瘤生长。总之，ABT-737 和 TRAIL 的合理组合共同触发 tBid 线粒体积累和凋亡。这种方法为靶向胶质母细胞瘤的凋亡途径提供了一种有前途的策略，值得进一步研究。
