Effects of Ligand Activation of Peroxisome Proliferator-Activated Receptor γ in Granulosa Cell Tumours — ASN Events

Effects of Ligand Activation of Peroxisome Proliferator-Activated Receptor γ in Granulosa Cell Tumours (#192)

Simon Chu 1 , Dilys TH Leung 1 , Maria Alexiadis 1 , Peter J Fuller 1
  1. Prince Henry's Institute, Clayton, VIC, Australia

Granulosa cell tumours (GCT) of the ovary are rare, hormonally-active neoplasms characterised by an indolent course and late relapse. Using a panel of GCT and two GCT-derived cell lines, our investigations have established that the critical pro-survival NF-κB signalling pathway is activated in GCT, and that inhibition of this pathway promotes apoptosis1. Peroxisome proliferator-activated receptor-gamma (PPARγ), a transcription factor that impedes proliferation and promotes terminal differentiation, is highly expressed in GCT and thus presents a potential therapeutic target2. Overexpression of PPARγ in GCT suggests resistance to the actions of PPARγ. We have found that this is due to transrepression by NF-κB. We have shown previously that abrogation of NF-κB signalling in GCT-derived cell lines enables PPARγ agonists to initiate apoptosis. Intriguingly, a key NF-κB-induced protein, the X-linked inhibitor of apoptosis protein (XIAP), is also highly expressed in GCT and blocks apoptosis. As XIAP inhibits key portions of the apoptotic pathways, it is an attractive therapeutic target. We hypothesise that combined targeting of PPARγ and XIAP presents a potential novel therapeutic strategy for the treatment of GCT. We investigated whether XIAP inhibition would sensitise GCT cells to PPARγ-mediated apoptosis. Treatment of GCT-derived KGN cells for 24 hours with either 20μM troglitazone (PPARγ agonist), 25μM embelin (XIAP inhibitor) or 500nM CmpA (a small molecule Smac mimetic that specifically antagonises XIAP) alone does not induce apoptosis. However, when activation of PPARγ was combined with inactivation of XIAP, we observed a significant decrease in cell proliferation and viability, characterised by a significant increase in apoptosis after 8 hours. Similar results were observed for another GCT-derived cell line, COV434. We conclude that, while the use of PPARγ agonists may have potential for treating GCT, a combination of therapies involving the abrogation of XIAP may be of greater efficacy.

  1. Transrepression of estrogen receptor beta signaling by nuclear factor-kappab in ovarian granulosa cells. Chu S, Nishi Y, Yanase T, Nawata H, Fuller PJ. Mol Endocrinol. 18(8):1919-28 2004.
  2. Nuclear receptor profiling of ovarian granulosa cell tumors. Alexiadis M, Eriksson N, Jamieson S, Davis M, Drummond AE, Chu S, Clyne CD, Muscat GE, Fuller PJ. Horm Cancer. 2(3):157-69 2011.