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)-γ, in a GCT-derived cell line, KGN. Both PPARγ and XIAP are overexpressed in human GCT. The inhibition of XIAP with the restoration of PPARγ 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 PPARγ using in silico screening. Chromatin immunoprecipitation confirmed the direct binding of PPARγ on the promoter region of SCD, with increased binding in the CmpdA/RGZ/RA-treated KGN cells. Because PPARγ 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 PPARγ activity.
journal_name
J Proteome Resjournal_title
Journal of proteome researchauthors
Leung DTH,Rainczuk A,Nguyen T,Stephens A,Silke J,Fuller PJ,Chu Sdoi
10.1021/acs.jproteome.8b00917subject
Has Abstractpub_date
2019-04-05 00:00:00pages
1691-1702issue
4eissn
1535-3893issn
1535-3907journal_volume
18pub_type
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