Paxilline enhances TRAIL-mediated apoptosis of glioma cells via modulation of c-FLIP, survivin and DR5
Paxilline enhances TRAIL-mediated apoptosis of glioma cells via modulation of c-FLIP, survivin and DR5
复制标题
DOI：
10.3858/emm.2011.43.1.003
复制
发表时间：
2011-01-31
影响因子：
12.8
通讯作者：
Choi, Kyeong Sook
中科院分区：
文献类型：
--
作者：
Kang, You Jung;Kim, In Young;Choi, Kyeong Sook
肿瘤坏死因子相关凋亡诱导配体（TRAIL）选择性诱导癌细胞凋亡，而不影响正常细胞。然而，许多癌细胞对TRAIL诱导的细胞死亡具有抗性。在这里，我们报告说，paxilline，吲哚生物碱从青霉paxilli，可以敏感各种胶质瘤细胞TRAIL介导的凋亡。在TRAIL耐药胶质瘤细胞系中，单独用TRAIL治疗导致半胱天冬酶-3部分加工成其p20中间体，而用TRAIL和亚毒性剂量的paxilline共同治疗导致半胱天冬酶-3完全加工成其活性亚基。Paxilline处理显著上调DR 5，TRAIL的受体，通过CHOP/GADD 153介导的过程。此外，paxilline治疗显着下调蛋白水平的短形式的细胞FLICE抑制蛋白（c-FLIPs）和半胱天冬酶抑制剂，生存素，通过蛋白酶体介导的降解。总之，这些结果表明，paxilline有效地敏感神经胶质瘤细胞TRAIL介导的凋亡，通过调节死亡受体介导的凋亡途径的多个组件。有趣的是，paxilline/TRAIL共处理不诱导正常星形胶质细胞的凋亡，也不影响这些细胞中CHOP、DR 5或存活素的蛋白水平。因此，联合治疗方案涉及paxilline和TRAIL可能提供一个有吸引力的策略，安全地治疗耐药胶质瘤。
Tumor necrosis factor-related apoptosis-induced ligand (TRAIL) induces apoptosis selectively in cancer cells while sparing normal cells. However, many cancer cells are resistant to TRAIL-induced cell death. Here, we report that paxilline, an indole alkaloid from Penicillium paxilli, can sensitize various glioma cells to TRAIL-mediated apoptosis. While treatment with TRAIL alone caused partial processing of caspase-3 to its p20 intermediate in TRAIL-resistant glioma cell lines, co-treatment with TRAIL and subtoxic doses of paxilline caused complete processing of caspase-3 into its active subunits. Paxilline treatment markedly upregulated DR5, a receptor of TRAIL, through a CHOP/GADD153-mediated process. In addition, paxilline treatment markedly downregulated the protein levels of the short form of the cellular FLICE-inhibitory protein (c-FLIPs) and the caspase inhibitor, survivin, through proteasome-mediated degradation. Taken together, these results show that paxilline effectively sensitizes glioma cells to TRAIL-mediated apoptosis by modulating multiple components of the death receptor-mediated apoptotic pathway. Interestingly, paxilline/TRAIL co-treatment did not induce apoptosis in normal astrocytes, nor did it affect the protein levels of CHOP, DR5 or survivin in these cells. Thus, combined treatment regimens involving paxilline and TRAIL may offer an attractive strategy for safely treating resistant gliomas.