Article ID Journal Published Year Pages File Type
5558247 Toxicology and Applied Pharmacology 2017 12 Pages PDF
Abstract

•Quinacrine induces U937 cell apoptosis via upregulation of BAX.•Quinacrine induces FOXP3 expression via p38 MAPK activation and ERK inactivation.•FOXP3-mediated miR-183 expression reduces β-TrCP mRNA stability.•Suppression of β-TrCP-mediated SP1 degradation increases BAX expression.•Quinacrine elicits FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation.

Quinacrine, which is clinically used as an antimalarial drug, has anti-cancer activity. However, mechanism underlying its cytotoxic effect remains to be completely elucidated. In the present study, we investigated the cytotoxic effect of quinacrine on human leukemia U937 cells. Quinacrine-induced apoptosis of U937 cells was accompanied with ROS generation, mitochondrial depolarization, and BAX upregulation. Quinacrine-treated U937 cells showed ROS-mediated p38 MAPK activation and ERK inactivation, which in turn upregulated FOXP3 transcription. FOXP3-mediated miR-183 expression decreased β-TrCP mRNA stability and suppressed β-TrCP-mediated SP1 degradation, thus increasing SP1 expression in U937 cells. Upregulated SP1 expression further increased BAX expression. BAX knock-down attenuated quinacrine-induced mitochondrial depolarization and increased the viability of quinacrine-treated cells. Together, our data indicate that quinacrine-induced apoptosis of U937 cells is mediated by mitochondrial alterations triggered by FOXP3/miR-183/β-TrCP/SP1 axis-mediated BAX upregulation.

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