Combined PPARγ Activation and XIAP Inhibition as a Potential Therapeutic Strategy for Ovarian Granulosa Cell Tumors

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 (PPAR gamma), and constitutive activity of the NF kappa B and API signaling pathways in GCT. PPAR gamma presents as a potential therapeutic target as it impedes proliferation and promotes terminal differentiation of granulosa cells. However, resistance to the actions of PPAR gamma is caused by NF kappa B transrepression in GCT-derived cell lines, KGN and COV434. We showed that abrogation of NFkB signaling in GCT cells enables PPAR gamma agonists to initiate apoptosis. In addition, we observed overexpression of an NF kappa B-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 antitumor effects of combined XIAP inhibition using Smacmimetics and PPAR gamma activation using thiazolidinediones (TZD) in the GCT-derived cells. Transactivation assays revealed that NFkB transrepression of PPAR gamma can be relieved by NF kappa B 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 cotreatment also delayed cell invasion, upregulated proapoptotic genes, and compromised cell metabolism in KGN cells. This study provides evidence that PPAR gamma and XIAP cotreatment has antineoplastic effects in GCT. As therapeutics that target these proteins are already in clinical or preclinical use, expedient translation to the clinic is possible.