Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.
Loss of caspase-3 sensitizes colon cancer cells to genotoxic stress via RIP1-dependent necrosis.
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DOI：
10.1038/cddis.2015.104
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发表时间：
2015-04-23
影响因子：
9
通讯作者：
Yu J
中科院分区：
文献类型：
--
作者：
Brown MF;Leibowitz BJ;Chen D;He K;Zou F;Sobol RW;Beer-Stolz D;Zhang L;Yu J
Caspase-3是最著名的细胞凋亡的执行者caspase。我们产生了caspase-3基因敲除(C3KO)和击倒的人结肠癌细胞，并发现它们对DNA损伤剂包括5-氟尿嘧啶(5-FU)、依托泊苷和喜树碱出人意料地敏感。C3KO移植瘤对5-FU的治疗反应增强，细胞死亡增加。C3KO细胞表现出完整的凋亡和caspase-7和caspase-9的激活，caspase-8的加工受损，并在DNA损伤剂诱导下发生坏死。这种形式的坏死与HMGB1的释放和ROS的产生有关，并被RIP1、MLKL1或caspase-8的基因或药物抑制，但不是泛caspase或RIP3的抑制剂。经5-FU处理后，形成了一个z-VAD抗性的前caspase-8/RIP1/FADD复合体，该复合体被caspase-3 KO强烈稳定。这些数据显示了caspase-3在caspase-8处理和抑制DNA损伤诱导的坏死中的关键作用，并为肿瘤细胞的化疗增敏提供了一种潜在的新途径。
Caspase-3 is the best known executioner caspase in apoptosis. We generated caspase-3 knockout (C3KO) and knockdown human colorectal cancer cells, and found that they are unexpectedly sensitized to DNA-damaging agents including 5-fluorouracil (5-FU), etoposide, and camptothecin. C3KO xenograft tumors also displayed enhanced therapeutic response and cell death to 5-FU. C3KO cells showed intact apoptosis and activation of caspase-7 and -9, impaired processing of caspase-8, and induction of necrosis in response to DNA-damaging agents. This form of necrosis is associated with HMGB1 release and ROS production, and suppressed by genetic or pharmacological inhibition of RIP1, MLKL1, or caspase-8, but not inhibitors of pan-caspases or RIP3. 5-FU treatment led to the formation of a z-VAD-resistant pro-caspase-8/RIP1/FADD complex, which was strongly stabilized by caspase-3 KO. These data demonstrate a key role of caspase-3 in caspase-8 processing and suppression of DNA damage-induced necrosis, and provide a potentially novel way to chemosensitize cancer cells.