Norcantharidin induces mitochondrial-dependent apoptosis through Mcl-1 inhibition in human prostate cancer cells

Abstract

Norcantharidin (NCTD) is the demethylated form of cantharidin that exhibits anticancer potential in many cancer cell types. Recent reports suggest that NCTD targeting ROS/AMPK and DNA replication signaling pathway could be an effective strategy for the treatment of PCa cells. However, supportive evidence is limited to the effect of NCTD that induction of apoptosis through suppression of the Mcl-1. Here, we show that NCTD induced PCa cell apoptosis and triggered caspase activation, which was associated with mitochondria dysfunction. Mechanistic investigations suggested that NCTD modulated the Akt signaling via increased nuclear translocation and interaction with the myeloid cell leukemia-1 (Mcl-1) promoter by FOXO4, resulting in an apoptotic effect. Moreover, miR-320d, which targets Mcl-1, was significantly upregulated after NCTD treatment. Overexpression of miR-320d by NCTD induced mitochondria dysfunction and apoptosis, which was notably attenuated with a miR-320d inhibitor. In vivo xenograft analysis revealed that NCTD significantly reduced tumor growth in mice with PC3 tumor xenografts. Taken together, our results provide new insights into the critical role of NCTD in suppressing Mcl-1 via epigenetic upregulation of miR-320d, resulting in PCa cell apoptosis.

Keywords: Apoptosis; Mitochondria dysfunction; Myeloid cell leukemia-1; Norcantharidin; Prostate cancer cells; miR-320d.