title: Dephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway.
abstract: 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.
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yanhao
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Ruoqiu
authors.initials: R
authors.lastname: Fu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Li
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Hongwei
authors.initials: H
authors.lastname: Zhang
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Hu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yibiao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Xin
authors.initials: X
authors.lastname: Liu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Yunong
authors.initials: Y
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines (China Pharmaceutical University), Nanjing, China.
authors.forename: Ehu
authors.initials: E
authors.lastname: Liu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D000935:Antifungal Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002569:Cerulenin / Q000494:pharmacology*; D006801:Humans; D007938:Leukemia / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D048670:MAP Kinase Kinase 4 / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000378:metabolism*; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D051339:Actin Depolymerizing Factors; D000935:Antifungal Agents; D014408:Biomarkers, Tumor; D002569:Cerulenin; D051057:Proto-Oncogene Proteins c-akt; C515851:ROCK1 protein, human; D054460:rho-Associated Kinases; D048670:MAP Kinase Kinase 4
keywords: Akt; ROCK1; apoptosis; cerulenin; cofilin