Abstract
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.
Highlights
Fatty acid synthase (FAS) is a metabolic enzyme that catalyzes the terminal steps in long chain saturated fatty acid synthesis [1]
Cerulenin had little or no effect on the expression of total or phosphorylated mTOR, ERK, or p38 MAPK. These findings suggested that activation of ROCK1, inactivation of Akt, and activation of the JNK pathway were important for cerulenin-induced mitochondrial injury and apoptosis in leukemia cells
Knockdown of ROCK1 dramatically abrogated ceruleninmediated cytochrome c release, caspase-3 and -9 cleavage/activation, poly ADP ribose polymerase (PARP) degradation, and apoptosis (Figure 6G). These results suggested that the ROCK1/ Akt/JNK signaling pathway was functionally important for cerulenin-mediated cofilin dephosphorylation and mitochondrial translocation as well as apoptosis in human leukemia cells
Summary
Fatty acid synthase (FAS) is a metabolic enzyme that catalyzes the terminal steps in long chain saturated fatty acid synthesis [1]. The metabolic properties of cancer cells differ from those of normal cells in that cancer cells are more dependent on fatty acid synthesis for proliferation [2]. FAS expression in normal cells is generally very low or undetectable whereas it is highly expressed in most human cancer cells [3]. This difference suggests that targeting metabolic enzymes such as FAS could improve the efficacy of cancer therapy. Recent studies using pharmacologic inhibitors against FAS have shown that inhibition of FAS activity results in severe growth arrest and apoptosis in various types of tumor cells [4]. Several FAS inhibitors including cerulenin, C75, orlistat, C93, and GSK 837149A have shown antitumor activity [5]
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