Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells.
Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells.
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DOI：
10.1371/journal.pone.0154605
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发表时间：
2016
期刊：
影响因子：
3.7
通讯作者：
Gu Y
中科院分区：
文献类型：
--
作者：
Huo H;Zhou Z;Qin J;Liu W;Wang B;Gu Y
我们在这里评估了电压依赖性阴离子通道（VDAC）结合化合物erastin的潜在抗结直肠癌活性。我们的体外研究表明，erastin对多种人结直肠癌细胞系产生有效的细胞毒性作用，可能通过诱导氧化应激和caspase-9依赖的细胞凋亡。此外，在erastin处理的癌细胞中观察到线粒体渗透性转换孔（mPTP）开放，这通过VDAC-1和亲环蛋白-D（Cyp-D）缔合、线粒体去极化和细胞色素C释放来证明。半胱天冬酶抑制剂、ROS清除剂MnTBAP和mPTP阻断剂（桑菲林A、环孢菌素A和邦格列酸）以及shRNA介导的VDAC-1敲低均显著减弱了erastin诱导的结直肠癌细胞的细胞毒性和凋亡。另一方面，VDAC-1的过表达增加了erastin诱导的ROS产生、mPTP开放和结直肠癌细胞凋亡。体内研究表明，在耐受性良好的剂量下腹腔注射erastin可显著抑制严重联合免疫缺陷（SCID）小鼠中HT-29异种移植物的生长。总之，这些结果表明erastin对结肠直肠癌细胞具有细胞毒性和促凋亡作用。Erastin有望成为一种新型的抗结直肠癌药物。
We here evaluated the potential anti-colorectal cancer activity by erastin, a voltage-dependent anion channel (VDAC)-binding compound. Our in vitro studies showed that erastin exerted potent cytotoxic effects against multiple human colorectal cancer cell lines, possibly via inducing oxidative stress and caspase-9 dependent cell apoptosis. Further, mitochondrial permeability transition pore (mPTP) opening was observed in erastin-treated cancer cells, which was evidenced by VDAC-1 and cyclophilin-D (Cyp-D) association, mitochondrial depolarization, and cytochrome C release. Caspase inhibitors, the ROS scavenger MnTBAP, and mPTP blockers (sanglifehrin A, cyclosporin A and bongkrekic acid), as well as shRNA-mediated knockdown of VDAC-1, all significantly attenuated erastin-induced cytotoxicity and apoptosis in colorectal cancer cells. On the other hand, over-expression of VDAC-1 augmented erastin-induced ROS production, mPTP opening, and colorectal cancer cell apoptosis. In vivo studies showed that intraperitoneal injection of erastin at well-tolerated doses dramatically inhibited HT-29 xenograft growth in severe combined immunodeficient (SCID) mice. Together, these results demonstrate that erastin is cytotoxic and pro-apoptotic to colorectal cancer cells. Erastin may be further investigated as a novel anti-colorectal cancer agent.