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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
2019-04-05
Journal of Proteome Research
Journal Article
18
4
1691-1702
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.
ACS
Inflammation
10.1021/acs.jproteome.8b00917
30706710
Refer to copyright notice on published article.

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Creation Date 2019-04-26 10:14:44 Last Modified 2019-04-26 01:57:29