Combined PPARg activation and XIAP inhibition as a potential therapeutic strategy for ovarian granulosa cell tumors
Leung, DTH; Nguyen, T; Oliver, EM; Matti, J; Alexiadis, M; Silke, J; Jobling, TW; Fuller, PJ; Chu, S
Molecular Cancer Therapeutics
Ovarian granulosa cell tumors (GCT) are characterized by indolent growth and late relapse. No therapeutic modalities aside from surgery have proven effective. We previously reported overexpression of the nuclear receptor, peroxisome proliferator-activated receptor-gamma (PPARg) and constitutive activity of the NFkB and AP1 signaling pathways in GCT. PPARg presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPARg is caused by NFkB transrepression in GCT-derived cell lines, KGN and COV434. We showed that abrogation of NFkB signaling in GCT cells enables PPARg agonists to initiate apoptosis. Additionally, we observed overexpression of an NFkB induced gene, X-linked inhibitor of apoptosis protein (XIAP), in GCT and GCT-derived cells. XIAP is an attractive therapeutic target due to its role in inhibiting the apoptotic pathway. We investigated the anti-tumor effects of combined XIAP inhibition using Smac-mimetics and PPARg activation using thiazolidinediones (TZD) in the GCT-derived cells. Transactivation assays revealed that NFkB transrepression of PPARg can be relieved by NFkB or XIAP inhibition. Combined Smac-mimetic and TZD significantly induced apoptosis, reduced cell viability and proliferation in KGN cells in monolayer and 3D spheroid culture, and in GCT explant models. The Smac-mimetic and TZD co-treatment also delayed cell invasion, upregulated pro-apoptotic genes and compromised cell metabolism in KGN cells. This study provides evidence that PPARg and XIAP co-treatment has anti-neoplastic effects in GCT. As therapeutics that target these proteins are already in clinical or pre-clinical use, expedient translation to the clinic is possible.