Targeting XIAP and PPARγ in granulosa cell tumors alters metabolic signaling

Tan Hung Leung, Adam Rainczuk, Trang Nguyen, Andrew Stephens, John Silke, Peter J. Fuller, Simon Chu

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Ovarian granulosa cell tumors (GCT) are hormonally-active cancers characterized by indolent growth and late, invasive relapse. No therapies have yet proven to be efficacious. We previously reported that inhibition of the anti-apoptotic 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. Inhibition of XIAP with 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 (SILAC), 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. As PPARγ plays a pivotal role in lipid and glucose metabolism, upregulation of proteins associated with metabolic processes such as SCD is consistent with the restoration of PPARγ activity.
Original languageEnglish
Pages (from-to)1691-1701
Number of pages11
JournalJournal of Proteome Research
Volume18
Issue number4
DOIs
Publication statusPublished - 5 Apr 2019

Keywords

  • apoptosis
  • granulosa cell tumors
  • ovary
  • proteomics
  • receptor binding

Cite this

Leung, Tan Hung ; Rainczuk, Adam ; Nguyen, Trang ; Stephens, Andrew ; Silke, John ; Fuller, Peter J. ; Chu, Simon. / Targeting XIAP and PPARγ in granulosa cell tumors alters metabolic signaling. In: Journal of Proteome Research. 2019 ; Vol. 18, No. 4. pp. 1691-1701.
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Targeting XIAP and PPARγ in granulosa cell tumors alters metabolic signaling. / Leung, Tan Hung; Rainczuk, Adam; Nguyen, Trang; Stephens, Andrew; Silke, John; Fuller, Peter J.; Chu, Simon.

In: Journal of Proteome Research, Vol. 18, No. 4, 05.04.2019, p. 1691-1701.

Research output: Contribution to journalArticleResearchpeer-review

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T1 - Targeting XIAP and PPARγ in granulosa cell tumors alters metabolic signaling

AU - Leung, Tan Hung

AU - Rainczuk, Adam

AU - Nguyen, Trang

AU - Stephens, Andrew

AU - Silke, John

AU - Fuller, Peter J.

AU - Chu, Simon

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Y1 - 2019/4/5

N2 - Ovarian granulosa cell tumors (GCT) are hormonally-active cancers characterized by indolent growth and late, invasive relapse. No therapies have yet proven to be efficacious. We previously reported that inhibition of the anti-apoptotic 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. Inhibition of XIAP with 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 (SILAC), 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. As PPARγ plays a pivotal role in lipid and glucose metabolism, upregulation of proteins associated with metabolic processes such as SCD is consistent with the restoration of PPARγ activity.

AB - Ovarian granulosa cell tumors (GCT) are hormonally-active cancers characterized by indolent growth and late, invasive relapse. No therapies have yet proven to be efficacious. We previously reported that inhibition of the anti-apoptotic 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. Inhibition of XIAP with 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 (SILAC), 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. As PPARγ plays a pivotal role in lipid and glucose metabolism, upregulation of proteins associated with metabolic processes such as SCD is consistent with the restoration of PPARγ activity.

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KW - ovary

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