Targeting XIAP and PPARgamma in granulosa cell tumors alters metabolic signaling

Leung, DTH; Rainczuk, A; Nguyen, T; Stephens, A; Silke, J; Fuller, PJ; Chu, S

Author(s): Leung, DTH; Rainczuk, A; Nguyen, T; Stephens, A; Silke, J; Fuller, PJ; Chu, S;
Details: Publication Year 2019-04-05,Volume 18,Issue #4,Page 1691-1702
Journal Title: Journal of Proteome Research
Publication Type: Journal Article
Abstract: 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 PPARgamma and XIAP are overexpressed in human GCT. The inhibition of XIAP with the restoration of PPARgamma 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 PPARgamma using in silico screening. Chromatin immunoprecipitation confirmed the direct binding of PPARgamma on the promoter region of SCD, with increased binding in the CmpdA/RGZ/RA-treated KGN cells. Because PPARgamma 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 PPARgamma activity.
Publisher: ACS
Research Division(s): Inflammation
PubMed ID: 30706710
Publisher's Version: https://doi.org/10.1021/acs.jproteome.8b00917
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2019-04-26 10:14:44

Last Modified: 2019-04-26 01:57:29