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.
Highlights
Mitochondria are double membrane-bound organelles found in most eukaryotic cells, where they play essential and diverse roles in cellular physiology, including growth, division, energy metabolism, and apoptosis [1,2,3]
Erucin induces apoptosis and mitochondrial fission in human breast cancer cells First, we examined the effects of erucin on apoptosis and mitochondrial injury in human breast cancer MDAMB-231 and MCF-7 cells
Mitochondrial fission is related to the initiation of apoptosis [4, 12, 25], and we examined the effects of erucin on mitochondrial fission in both MDA-MB-231 and MCF-7 cells
Summary
Mitochondria are double membrane-bound organelles found in most eukaryotic cells, where they play essential and diverse roles in cellular physiology, including growth, division, energy metabolism, and apoptosis [1,2,3]. Mitochondria are elongated and filamentous, but they undergo extensive fragmentation during apoptosis [5]. Apoptotic fission is associated with remodeling of the cristae, which is characterized by the opening of their tubular junction. This process results in the complete release of proapoptotic factors, such as cytochrome c, which is required in the cytosol for the activation of downstream effector caspases [6]. Drp is a GTPase that causes scission of the mitochondrial outer membrane, resulting in fission of mitochondrial tubules into fragments [7, 8]. Drp translocates from the cytosol to the mitochondria and mediates mitochondrial fission prior to caspase activation and apoptosis [9]. The mechanism by which Drp is recruited to mitochondria remains unresolved
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