Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1.
Following cytochrome c release, autophagy is inhibited during chemotherapy-induced apoptosis by caspase 8-mediated cleavage of Beclin 1.
复制标题
细胞色素 c 释放后，在化疗诱导的细胞凋亡过程中，自噬受到 caspase 8 介导的 Beclin 1 裂解的抑制。
DOI：
10.1158/0008-5472.can-10-4475
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发表时间：
2011-05-15
期刊：
影响因子：
11.2
通讯作者：
Zhang L
中科院分区：
文献类型：
--
作者：
Li H;Wang P;Sun Q;Ding WX;Yin XM;Sobol RW;Stolz DB;Yu J;Zhang L
自噬是一种进化上保守的应激反应机制，通常发生在凋亡缺陷的癌细胞中，可以防止细胞死亡。在这项研究中，我们研究了癌细胞对化疗的反应中细胞凋亡和自噬如何相互影响。我们发现，细胞色素c（线粒体介导的细胞凋亡的关键调节剂）的促凋亡功能的特异性消除可增强化疗后的自噬。自噬的诱导需要 Beclin 1，并且与半胱天冬酶 8 在两个位点阻断 Beclin 1 裂解有关。为了研究 Beclin 1 裂解在抑制自噬和细胞存活中的作用，将 Beclin 1 的半胱天冬酶抗性突变体敲入 HCT116 结肠癌细胞中。 Beclin 1 突变体敲入导致自噬显着增加，并改善化疗后细胞的长期存活率，但不影响细胞凋亡和 caspase 激活。此外，Beclin 1 突变肿瘤对化疗的反应明显低于野生型肿瘤。这些结果表明，化疗诱导的细胞凋亡通过 Caspase 8 介导的 Beclin 1 裂解，在细胞色素 c 释放后的执行阶段抑制自噬。如果细胞凋亡无法执行，则由于 Caspase 缺乏 Beclin 1 裂解，自噬会被释放，并有助于癌细胞存活和治疗耐药。因此，Beclin 1可能是抑制自噬以使化疗增敏的有用靶标。
Autophagy is an evolutionarily conserved stress response mechanism that often occurs in apoptosis-defective cancer cells and can protect against cell death. In this study, we investigated how apoptosis and autophagy affect each other in cancer cells in response to chemotherapeutic treatment. We found that specific ablation of the proapoptotic function of cytochrome c, a key regulator of mitochondria-mediated apoptosis, enhanced autophagy following chemotherapeutic treatment. Induction of autophagy required Beclin 1, and was associated with blockage of Beclin 1 cleavage by caspase 8 at two sites. To investigate the role of Beclin 1 cleavage in the suppression of autophagy and cell survival, a caspase-resistant mutant of Beclin 1 was knocked into HCT116 colon cancer cells. Beclin 1 mutant knock-in resulted in markedly increased autophagy and improved long-term cell survival after chemotherapeutic treatment, but without affecting apoptosis and caspase activation. Furthermore, Beclin 1 mutant tumors were significantly less responsive to chemotherapeutic treatment than wild-type tumors. These results demonstrate that chemotherapy-induced apoptosis inhibits autophagy at the execution stage subsequent to cytochrome c release through caspase 8-mediated cleavage of Beclin 1. If apoptosis fails to execute, autophagy is unleashed due to lack of Beclin 1 cleavage by caspases, and can contribute to cancer cell survival and therapeutic resistance. Therefore, Beclin 1 may be a useful target for inhibiting autophagy to sensitize chemotherapy.