Ligand-Activated Peroxisome Proliferator-Activated Receptor β/δ Modulates Human Endometrial Cancer Cell Survival

Endometrial cancer is the fourth most common malignancy among women and is a major cause of morbidity contributing to approximately 8,200 annual deaths in the USA. Despite advances to the understanding of endometrial cancer, novel interventions for the disease are necessary given that many tumors become refractory to therapy. As a strategy to identify novel therapies for endometrial carcinoma, in this study, we examined the contribution of the peroxisome proliferator-activated receptor beta/delta (PPAR beta/delta) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPAR beta/delta agonists, GW0742 and GW501516, PPAR beta/delta inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPAR beta/delta-induced effects on cell proliferation and apoptosis was demonstrated using PPAR beta/delta-selective antagonists and PPAR beta/delta small interfering RNA in combination with PPAR beta/delta-selective agonists. Furthermore, we showed that PPAR beta/delta activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3 beta (GSK3 beta) dephosphorylation, and increased beta-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPAR beta/delta activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3 beta/beta-catenin pathway. These findings warrant further investigation of PPAR beta/delta as a therapeutic target in endometrial cancer.