Gamma secretase inhibitors inhibit ovarian cancer development and enhance olaparib's anti-ovarian cancer activity and its mechanism

Abstract

BackgroundOvarian cancer is the fifth leading cause of cancer-related deaths in women. Although cytoreductive surgery combined with chemotherapy and / or targeted therapy has achieved a certain effect, but advanced patients have limited clinical benefits and are prone to relapse. Among them, Notch / jagged1 and Wnt / {beta}-catenin signal transduction plays an important role in the development of ovarian cancer and chemotherapy resistance, and it is very important to find new effective therapeutic drugs to inhibit tumor development and increase tumor chemotherapy sensitivity. MethodsTo establish ovarian cancer xenotransplantation model, to detect the effects of {gamma}-secretase inhibitor, olaparib and combination drugs on the development of ovarian cancer, and to detect the proliferation and apoptosis of ovarian cancer cells with {gamma}-secretase inhibitor, olaparib and combination drugs .After knocking down Jagged1 or {beta}-catenin, the protein expression levels of related signaling pathways under different drug treatments were analyzed by immunoblotting, and related gene expression changes were analyzed. ResultsDAPT reduced {beta}-catenin expression in a proteasome-synthetic pathway-dependent manner, thereby inhibiting the synthesis and transcription of Jagged1 protein, thereby inhibiting the expression of Notch signal transduction pathway-related proteins and gene transcription, inhibiting the activity of ovarian cancer cells and inducing cell apoptosis death, enhance the anti-ovarian cancer activity of olaparib. ConclusionDAPT inhibits cell proliferation, induces cell apoptosis, inhibits tumor development in vivo through {beta}-catenin / Jagged1 inhibition, and exerts anti-ovarian cancer activity sensitizing effect of olaparib.