Curdione induces G2/M phage arrest, apoptosis and autophagy via COX2 mediate IDO1 expression through PKCδ/ GSK3β/β-catenin pathway in human uterine leiomyosarcoma

Abstract Background Curdione, one of active ingredients of a traditional Chinese herb medicine-Curcuma zedoary, has been reported with beneficial therapeutic effects in lots of cancer types. However, the potential anti-cancer effect in uterine leiomyosarcoma (uLMS) and the underlying mechanisms are still unclear.Methods The aim of this study was to explore the potential effect and mechanisms of curdione on uLMS in vitro and vivo with uLMS cell lines and mouse xenograft tumor model respectively.Results Curdione triggered anti-proliferation effect in uLMS cell lines by inducing cell cycle arrest at G2/M phase, caspase-mediated cell apoptosis, and pro-death cell autophagy. Indoleamine-2,3-dioxygenase-1 (IDO1), which was dependent on cyclooxygenase-2 (COX2), mediated the anti-proliferation effect of curdione. Curdione down-regulated IDO1 expression and promoted the dephosphorylation of protein kinase c (PKC), glycogen synthase kinase-3 beta (GSK3β) and β-catenin in cell lines. PKC/GSK3β/β-catenin pathway responsible for constitutive IDO1 expression in uLMS. COX2 mediate the promotion effect of curdione on the PKC/GSK3β/β catenin pathway activity, which was detected by COX2 inhibitor, and further confirmed by COX2 siRNA and COX2 overexpression. The pathway activity was inhibited by COX2-siRNA and enhanced by COX2 overexpression. In turn, the pathway inhibitor suppressed IDO1 expression. The anti-proliferation effect of curdione on uterine leiomyosarcoma were further confirmed in vivo. Echoing to the results in vitro, the underline mechanism involved in COX2-mediated IDO1 down-regulation via PKCδ/GSK3β/β-catenin pathway.Conclusion COX2-mediated IDO1 down-regulation via PKCδ/GSK3β/β-catenin pathway involved in the anti-proliferation effect of curdione on uterine leiomyosarcoma in vitro and vivo.