title: Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis.
abstract: Cofilin is a member of the actin-depolymerizing factor (ADF) family protein, which plays an essential role in regulation of the mitochondrial apoptosis. It remains unclear how cofilin regulates the mitochondrial apoptosis. Here, we report for the first time that natural compound 4-methylthiobutyl isothiocyanate (erucin) found in consumable cruciferous vegetables induces mitochondrial fission and apoptosis in human breast cancer cells through the mitochondrial translocation of cofilin. Importantly, cofilin regulates erucin-induced mitochondrial fission by interacting with dynamin-related protein (Drp1). Knockdown of cofilin or Drp1 markedly reduced erucin-mediated mitochondrial translocation and interaction of cofilin and Drp1, mitochondrial fission, and apoptosis. Only dephosphorylated cofilin (Ser 3) and Drp1 (Ser 637) are translocated to the mitochondria. Cofilin S3E and Drp1 S637D mutants, which mimick the phosphorylated forms, suppressed mitochondrial translocation, fission, and apoptosis. Moreover, both dephosphorylation and mitochondrial translocation of cofilin and Drp1 are dependent on ROCK1 activation. In vivo findings confirmed that erucin-mediated inhibition of tumor growth in a breast cancer cell xenograft mouse model is associated with the mitochondrial translocation of cofilin and Drp1, fission and apoptosis. Our study reveals a novel role of cofilin in regulation of mitochondrial fission and suggests erucin as a potential drug for treatment of breast cancer.
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Guobing
authors.initials: G
authors.lastname: Li
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.affiliation: Cell & Molecular Biology, St. Jude Children's Research Hospital, Memphis TN 38105, USA.
authors.forename: Amit
authors.initials: A
authors.lastname: Budhraja
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Xiaoye
authors.initials: X
authors.lastname: Hu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Yibiao
authors.initials: Y
authors.lastname: Chen
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.affiliation: State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China.
authors.forename: Ehu
authors.initials: E
authors.lastname: Liu
authors.affiliation: College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
mesh_terms: D051339:Actin Depolymerizing Factors / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000378:metabolism*; D045744:Cell Line, Tumor; D034281:Dynamins; D005260:Female; D020558:GTP Phosphohydrolases / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation; D064593:Heterografts; D006801:Humans; D061986:MCF-7 Cells; D051379:Mice; D008819:Mice, Nude; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism*; D008928:Mitochondria / Q000378:metabolism*; D024101:Mitochondrial Proteins / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
chemical_list: D051339:Actin Depolymerizing Factors; D008869:Microtubule-Associated Proteins; D024101:Mitochondrial Proteins; D020558:GTP Phosphohydrolases; C110768:DNM1L protein, human; D034281:Dynamins