Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis.
Mitochondrial translocation and interaction of cofilin and Drp1 are required for erucin-induced mitochondrial fission and apoptosis.
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线粒体易位以及 cofilin 和 Drp1 的相互作用是芥酸诱导的线粒体裂变和细胞凋亡所必需的
DOI：
10.18632/oncotarget.2795
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发表时间：
2015-01-30
期刊：
影响因子：
--
通讯作者：
Gao N
中科院分区：
文献类型：
--
作者：
Li G;Zhou J;Budhraja A;Hu X;Chen Y;Cheng Q;Liu L;Zhou T;Li P;Liu E;Gao N
Cofilin是肌动蛋白解聚因子（ADF）家族的一员，在线粒体凋亡的调控中起重要作用。目前尚不清楚cofilin如何调节线粒体凋亡。在这里，我们报告的第一次，天然化合物4-甲基硫丁基异硫氰酸酯（芥酸）中发现的消费性十字花科蔬菜诱导线粒体分裂和凋亡的人乳腺癌细胞通过线粒体易位的丝切蛋白。重要的是，cofilin通过与动力蛋白相关蛋白（Drp 1）相互作用来调节芥酸诱导的线粒体分裂。cofilin或Drp 1的敲除显著减少了erucin介导的线粒体易位以及cofilin和Drp 1的相互作用、线粒体分裂和凋亡。只有去磷酸化的cofilin（Ser 3）和Drp 1（Ser 637）被转位到线粒体。Cofilin S3 E和Drp 1 S637 D突变体，模拟磷酸化形式，抑制线粒体易位，分裂和凋亡。此外，cofilin和Drp 1的去磷酸化和线粒体易位都依赖于ROCK 1的激活。体内研究结果证实，在乳腺癌细胞异种移植小鼠模型中，芥酸介导的肿瘤生长抑制与cofilin和Drp 1的线粒体易位、分裂和凋亡相关。我们的研究揭示了cofilin在调节线粒体分裂中的新作用，并表明erucin作为一种潜在的治疗乳腺癌的药物。
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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DOI：
10.1073/pnas.1208141109
发表时间：
2012-09-18
影响因子：
11.1
作者：
Beck, Henning;Flynn, Kevin;Knoell, Bernd
通讯作者：
Knoell, Bernd
影响因子：
5.2
作者：
Abbaoui, Besma;Riedl, Kenneth M.;Ralston, Robin A.;Thomas-Ahner, Jennifer M.;Schwartz, Steven J.;Clinton, Steven K.;Mortazavi, Amir
通讯作者：
Mortazavi, Amir
影响因子：
25
作者：
Gu, Jiaping;Lee, Chi Wai;Fan, Yanjie;Komlos, Daniel;Tang, Xin;Sun, Chicheng;Yu, Kuai;Hartzell, H. Criss;Chen, Gong;Bamburg, James R.;Zheng, James Q.
通讯作者：
Zheng, James Q.
影响因子：
12.4
作者：
Estaquier, J.;Arnoult, D.
通讯作者：
Arnoult, D.
影响因子：
20.1
作者：
Hong Z;Kutty S;Toth PT;Marsboom G;Hammel JM;Chamberlain C;Ryan JJ;Zhang HJ;Sharp WW;Morrow E;Trivedi K;Weir EK;Archer SL
通讯作者：
Archer SL