Targeting XIAP and PPARγ in granulosa cell tumors alters metabolic signaling.

Ovarian granulosa cell tumors (GCTs) are hormonally active cancers characterized by indolent growth and late, invasive relapse. No therapies have yet proven to be efficacious. We previously reported that the inhibition of the antiapoptotic X-linked inhibitor of apoptosis protein (XIAP) removes transrepression of the pro-proliferative nuclear receptor, peroxisome proliferator-activated receptor (PPAR)-gamma, in a GCT-derived cell line, KGN. Both PPAR gamma and XIAP are overexpressed in human GCT. The inhibition of XIAP with the restoration of PPARy signaling using a SMAC-mimetic (Compound A (CmpdA)) and rosiglitazone (RGZ)/retinoic acid (RA), respectively, reduced cell proliferation and induced apoptosis in the KGN cells. Utilizing stable isotope labeling with amino acids in cell culture, we identified 32 differentially expressed proteins in the KGN cells following the CmpdA/RGZ/RA-treatment, 22 of which were upregulated by >= 1.5 fold. Of these, stearoyl-CoA desaturase (SCD; 4.5-fold induction) was examined for putative binding sites for PPAR gamma using in silico screening. Chromatin immunoprecipitation confirmed the direct binding of PPAR gamma on the promoter region of SCD, with increased binding in the CmpdA/RGZ/RA-treated KGN cells. Because PPAR gamma plays a pivotal role in lipid and glucose metabolism, the upregulation of proteins associated with metabolic processes such as SCD is consistent with the restoration of PPAR gamma activity.