title: Mitochondrial translocation of cofilin is required for allyl isothiocyanate-mediated cell death via ROCK1/PTEN/PI3K signaling pathway.
abstract: BACKGROUND
  Cofilin is a member of the actin depolymerizing factor (ADF)/cofilin family, which regulates actin dynamics. Increasing evidence suggests that mitochondrial translocation of cofilin appears necessary for the regulation of apoptosis.
  
  
  RESULTS
  We report that allyl isothiocyanate (AITC) potently induces mitochondria injury and apoptosis. These events were accompanied by a loss of polymerized filamentous actin (F-actin) and increase in unpolymerized globular actin (G-actin). AITC also induces dephosphorylation of cofilin through activation of PP1 and PP2A. Only dephosphorylated cofilin binds to G-actin and translocates to mitochondria during AITC-mediated apoptosis. Mechanistic study revealed that interruption of ROCK1/PTEN/PI3K signaling pathway plays a critical role in AITC-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. Our in vivo study also showed that AITC-mediated inhibition of tumor growth of mouse leukemia xenograft model is in association with dephosphorylation of cofilin.
  
  
  CONCLUSIONS
  These findings support a model in which induction of apoptosis by AITC stems primarily from activation of ROCK1 and PTEN, and inactivation of PI3K, leading in turn to activation of PP1 and PP2A, resulting in dephosphorylation of cofilin, which binds to G-actin and translocates to mitochondria, culminating in the dysfunction of mitochondria, release of cytochrome c and apoptosis.
authors.affiliation: Department of Pharmacognosy, College of Pharmacy, 3rd Military Medical University, Chongqing 400038, China.
authors.forename: Guo-bing
authors.initials: GB
authors.lastname: Li
authors.forename: Qi
authors.initials: Q
authors.lastname: Cheng
authors.forename: Lei
authors.initials: L
authors.lastname: Liu
authors.forename: Ting
authors.initials: T
authors.lastname: Zhou
authors.forename: Chang-yu
authors.initials: CY
authors.lastname: Shan
authors.forename: Xiao-ye
authors.initials: XY
authors.lastname: Hu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: E-hu
authors.initials: EH
authors.lastname: Liu
authors.forename: Ping
authors.initials: P
authors.lastname: Li
authors.forename: Ning
authors.initials: N
authors.lastname: Gao
mesh_terms: D000199:Actins / Q000378:metabolism; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology* / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D002478:Cells, Cultured; D051338:Cofilin 1 / Q000378:metabolism*; D018922:HL-60 Cells; D006801:Humans; D017879:Isothiocyanates / Q000494:pharmacology* / Q000627:therapeutic use; D019169:Jurkat Cells; D007938:Leukemia / Q000188:drug therapy / Q000378:metabolism; D051379:Mice; D008819:Mice, Nude; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D020298:U937 Cells; D023041:Xenograft Model Antitumor Assays; D054460:rho-Associated Kinases / Q000378:metabolism*
chemical_list: D000199:Actins; D000970:Antineoplastic Agents; D051338:Cofilin 1; D017879:Isothiocyanates; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D054460:rho-Associated Kinases; C495810:CFL1 protein, human; C004471:allyl isothiocyanate; C515851:ROCK1 protein, human; C494929:PTEN protein, human
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