Thiazolidinediones augment anticancer effects of XIAP inhibition on human ovarian granulosa cell tumor-derived cells through PPARγ activation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 326-337-Hormone-Dependent Tumors
Bench to Bedside
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-327
Simon Chu*1, Edwina Oliver1, Dilys TH Leung1, Yong Nian Chee1, Maria Alexiadis1, John Silke2 and Peter J Fuller1
1Prince Henry's Institute, Clayton, Australia, 2Walter Eliza Hall Institute of Medical Research, Parkville, Australia
Ovarian Granulosa cell tumors (GCT) are hormonally-active neoplasms characterized by an indolent course and late relapse. The critical pro-survival NF-κB signaling pathway is activated in GCT (1), and inhibition of this pathway promotes apoptosis. Peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor that impedes proliferation and promotes terminal differentiation, is overexpressed in GCT (2) and may present a potential therapeutic target. Overexpression of PPARγ in GCT suggests resistance to the actions of PPARγ, our studies show that this is caused by NF-κB transrepression, and that abrogation of NF-κB signaling in GCT cells enables PPARγ/RXRα agonists to initiate apoptosis. Intriguingly, a key NF-κB-effector protein, the X-linked inhibitor of apoptosis protein (XIAP), is also highly expressed in GCT and blocks apoptosis. XIAP inhibits key portions of the apoptotic pathways and is an attractive therapeutic target. We hypothesize that combined targeting of PPARγ/RXRα and XIAP presents a novel therapeutic strategy for the treatment of GCT. To investigate this, GCT-derived KGN cells were treated for 24 hours with the PPARγ agonists troglitazone (TGZ) or rosiglitazone (RGZ) (co-treated with 9-cis-retinoic acid to activate RXRα), in combination with either 25mM embelin (XIAP inhibitor) or 500nM SM (a small molecule Smac mimetic that specifically antagonizes XIAP). On their own, the compounds do not induce apoptosis. However, activation of PPARγ combined with inactivation of XIAP caused a significant decrease in cell proliferation and viability, characterized by a significant increase in apoptosis after 24 hours. Similar results were observed for another GCT-derived cell line, COV434. Interestingly, these observations may also translate to ovarian epithelial cell cancers (EOC) as increased apoptosis was observed in cell lines derived from serous EOCs which expressed both XIAP and PPARγ, while EOC lines which do not express PPARγ showed no effect from the combined treatment. We are currently investigating the molecular mechanisms mediating the effect of the combination therapy using cell lines stably transduced with inducible shRNA against XIAP. We conclude that, while the use of PPARγ agonists may have potential for treating GCT, a combination therapy involving the abrogation of XIAP may be of greater efficacy. This combination therapy may also translate to other tumor types that express PPARγ and XIAP.

(1) Chu S et al., Mol Endocrinol. 2004; 18:1919. (2) Alexiadis M et al., Horm Cancer. 2011; 2:157.

Nothing to Disclose: SC, EO, DTL, YNC, MA, JS, PJF

*Please take note of The Endocrine Society's News Embargo Policy at http://www.endo-society.org/endo2013/media.cfm

Sources of Research Support: Ovarian Cancer Research Foundation P10-026