Erastin Disrupts Mitochondrial Permeability Transition Pore (mPTP) and Induces Apoptotic Death of Colorectal Cancer Cells.

Haizhong Huo,Zhiyuan Zhou,Bing Wang,Yan Gu,Wenyong Liu,Jian Qin,Cong Cao

doi:10.1371/journal.pone.0154605

Haizhong Huo, Zhiyuan Zhou + Show 5 more

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https://doi.org/10.1371/journal.pone.0154605

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Abstract

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.

Highlights

The colorectal cancer is the major contributor of cancer-related mortality both in China [1] and around the world [2,3]
Mitochondrial permeability transition pore is a multi-protein channel complex lying in the mitochondria, whose main function is to maintain the balance of mitochondrial respiratory chain [12]. mPTP is primarily composed of three proteins: including voltage
We showed that erastin was cytotoxic and pro-apoptotic to colorectal cancer cells, possibly via disrupting mPTP

Summary

Introduction

The colorectal cancer is the major contributor of cancer-related mortality both in China [1] and around the world [2,3]. It is estimated that over 100,000 new cases of colorectal cancer are diagnosed each year, which cause over 50,000 deaths annually [4]. Chemotherapy has been widely-utilized for treatment of colorectal cancer, drug resistance and/or off-target toxicity limit the efficiency of current chemo-drugs [5,6,7]. Our group [8,9] and others [10,11] have been focusing on the development of novel and more efficient anti-colorectal cancer agents. Mitochondrial permeability transition pore (mPTP) is a multi-protein channel complex lying in the mitochondria, whose main function is to maintain the balance of mitochondrial respiratory chain [12]. MPTP is primarily composed of three proteins: including voltage-.

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