Dephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway
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Yanhao Zhang1,*, Ruoqiu Fu1,*, Yanxia Liu1, Jing Li1, Hongwei Zhang1, Xiaoye Hu1, Yibiao Chen1, Xin Liu1, Yunong Li1, Ping Li2, Ehu Liu2, Ning Gao1
1College of Pharmacy, 3rd Military Medical University, Chongqing, China
2State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, China
*These authors contributed equally to this work
Ning Gao, e-mail: [email protected]
Ehu Liu, e-mail: [email protected]
Keywords: cofilin, ROCK1, Akt, cerulenin, apoptosis
Received: September 27, 2015 Accepted: February 18, 2016 Published: March 08, 2016
In this study, we determined that cerulenin, a natural product inhibitor of fatty acid synthase, induces mitochondrial injury and apoptosis in human leukemia cells through the mitochondrial translocation of cofilin. Only dephosphorylated cofilin could translocate to mitochondria during cerulenin-induced apoptosis. Disruption of the ROCK1/Akt/JNK signaling pathway plays a critical role in the cerulenin-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. In vivo studies demonstrated that cerulenin-mediated inhibition of tumor growth in a mouse xenograft model of leukemia was associated with mitochondrial translocation of cofilin and apoptosis. These data are consistent with a hierarchical model in which induction of apoptosis by cerulenin primarily results from activation of ROCK1, inactivation of Akt, and activation of JNK. This leads to the dephosphorylation and mitochondrial translocation of cofilin and culminates with cytochrome c release, caspase activation, and apoptosis. Our study has revealed a novel role of cofilin in the regulation of mitochondrial injury and apoptosis and suggests that cerulenin is a potential drug for the treatment of leukemia.
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