c-FLIP inhibits chemotherapy-induced colorectal cancer cell death
c-FLIP inhibits chemotherapy-induced colorectal cancer cell death
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DOI：
10.1038/sj.onc.1209122
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发表时间：
2006-02-01
期刊：
影响因子：
8
通讯作者：
Johnston, PG
中科院分区：
文献类型：
--
作者：
Longley, DB;Wilson, TR;Johnston, PG
FLIP 抑制 Fas 和 DR5 等死亡受体介导的 caspase 8 激活和细胞凋亡。我们研究了 c-FLIP 对结直肠癌 (CRC) 化疗（5-氟尿嘧啶、奥沙利铂和伊立替康）的细胞凋亡反应的影响。同时下调两个 c-FLIP 剪接形成 c-FLIPL 和 c-FLIPS，与 siRNA 协同增强 p53 野生型 (HCT116p53(+/+)，RKO)、无效 (HCT116p53(-/-)) 和突变型 (H630) CRC 细胞系中化疗诱导的细胞凋亡。此外，c-FLIPL而非c-FLIPS的过表达可有效抑制HCT116p53(-/-)细胞中化疗诱导的细胞凋亡，这表明c-FLIPL是介导化疗耐药性中更重要的剪接形式。为了支持这一点，专门针对 c-FLIPL 的 siRNA 以类似于针对两种剪接形式的 siRNA 的方式协同增强了化疗诱导的细胞凋亡。抑制 caspase 8 可阻断 c-FLIP 靶向 (FT) siRNA 和化疗诱导的细胞凋亡增强。此外，我们发现下调细胞表面 DR5（而非 Fas）也能抑制 FT siRNA 和化疗诱导的细胞凋亡。有趣的是，这些效应并不依赖于 DR5 的配体 TRAIL 的激活。这些结果表明，c-FLIP 抑制 CRC 细胞化疗反应中不依赖 TRAIL 的、依赖 DR5 和 caspase 8 的细胞凋亡。此外，靶向 c-FLIP 与现有化疗相结合可能具有治疗 CRC 的治疗潜力。
FLIP inhibits caspase 8 activation and apoptosis mediated by death receptors such as Fas and DR5. We studied the effect of c-FLIP on the apoptotic response to chemotherapies used in colorectal cancer (CRC) (5-fluorouracil, oxaliplatin and irinotecan). Simultaneous downregulation of both c-FLIP splice forms c-FLIPL and c-FLIPS with siRNA synergistically enhanced chemotherapy-induced apoptosis in p53 wild-type (HCT116p53(+/+), RKO), null (HCT116p53(-/-)) and mutant (H630) CRC cell lines. Furthermore, overexpression of c-FLIPL, but not c-FLIPS, potently inhibited apoptosis induced by chemotherapy in HCT116p53(-/-) cells, suggesting that c-FLIPL was the more important splice form in mediating chemoresistance. In support of this, siRNA specifically targeted against c-FLIPL synergistically enhanced chemotherapy-induced apoptosis in a manner similar to the siRNA targeted against both splice forms. Inhibition of caspase 8 blocked the enhanced apoptosis induced by c-FLIP-targeted (FT) siRNA and chemotherapy. Furthermore, we found that downregulating cell surface DR5, but not Fas, also inhibited apoptosis induced by FT siRNA and chemotherapy. Interestingly, these effects were not dependent on activation of DR5 by its ligand TRAIL. These results indicate that c-FLIP inhibits TRAIL-independent, DR5- and caspase 8-dependent apoptosis in response to chemotherapy in CRC cells. Moreover, targeting c-FLIP in combination with existing chemotherapies may have therapeutic potential for the treatment of CRC.