Open AccessDephosphorylation and mitochondrial translocation of cofilin sensitizes human leukemia cells to cerulenin-induced apoptosis via the ROCK1/Akt/JNK signaling pathway
Author(s) -
Yanhao Zhang,
Ruoqiu Fu,
Yanxia Liu,
Jing Li,
Hongwei Zhang,
Xiaoye Hu,
Yibiao Chen,
Xin Liu,
Yug Li,
Ping Li,
EHu Liu,
Ning Gao
Publication year - 2016
Publication title -
oncotarget
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.373
H-Index - 127
ISSN - 1949-2553
DOI - 10.18632/oncotarget.7994
Subject(s) - cerulenin , microbiology and biotechnology , apoptosis , cofilin , dephosphorylation , protein kinase b , rock1 , mitochondrion , intrinsic apoptosis , biology , chemistry , signal transduction , cancer research , phosphorylation , programmed cell death , fatty acid synthase , caspase , rhoa , biochemistry , cell , actin cytoskeleton , phosphatase , fatty acid , cytoskeleton
In this study, we determined that cerulenin, a natural product inhibitor of fatty acid synthase, induces mitochondrial injury and apoptosis in human leukemia cells through the mitochondrial translocation of cofilin. Only dephosphorylated cofilin could translocate to mitochondria during cerulenin-induced apoptosis. Disruption of the ROCK1/Akt/JNK signaling pathway plays a critical role in the cerulenin-mediated dephosphorylation and mitochondrial translocation of cofilin and apoptosis. In vivo studies demonstrated that cerulenin-mediated inhibition of tumor growth in a mouse xenograft model of leukemia was associated with mitochondrial translocation of cofilin and apoptosis. These data are consistent with a hierarchical model in which induction of apoptosis by cerulenin primarily results from activation of ROCK1, inactivation of Akt, and activation of JNK. This leads to the dephosphorylation and mitochondrial translocation of cofilin and culminates with cytochrome c release, caspase activation, and apoptosis. Our study has revealed a novel role of cofilin in the regulation of mitochondrial injury and apoptosis and suggests that cerulenin is a potential drug for the treatment of leukemia.