Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis
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Guobing Li1,*, Jing Zhou1,*, Amit Budhraja3, Xiaoye Hu1, Yibiao Chen1, Qi Cheng1, Lei Liu1, Ting Zhou1, Ping Li2, Ehu Liu2, Ning Gao1
1College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China
2State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing 210009, China
3Cell & Molecular Biology, St. Jude Children’s Research Hospital, Memphis TN 38105, USA
*These authors have contributed equally to this work
Ning Gao, e-mail: [email protected]
Ehu Liu, e-mail: [email protected]
Keywords: Cofilin, Drp1, mitochondrial fission, erucin, apoptosis
Received: September 18, 2014 Accepted: November 20, 2014 Published: December 16, 2014
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.
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