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

J. J. Ma, D. Monsivais, M. T. Dyson, J. S. Coon, S. Malpani, M. Ono, H. Zhao, H. Xin, M. E. Pavone, J. J. Kim, D. Chakravarti, S. E. Bulun

Research output: Contribution to journalArticlepeer-review

6 Scopus citations

Abstract

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 β/δ (PPARβ/δ) to endometrial cancer cell proliferation and apoptosis. We found that when activated with the highly selective PPARβ/δ agonists, GW0742 and GW501516, PPARβ/δ inhibited the proliferation and markedly induced the apoptosis of three endometrial cancer cell lines. The specificity of the PPARβ/δ-induced effects on cell proliferation and apoptosis was demonstrated using PPARβ/δ-selective antagonists and PPARβ/δ small interfering RNA in combination with PPARβ/δ-selective agonists. Furthermore, we showed that PPARβ/δ activation increased phosphatase and tensin homolog expression, which led to protein kinase B (AKT) and glycogen synthase kinase-3β (GSK3β) dephosphorylation, and increased β-catenin phosphorylation associated with its degradation. Overall, our data suggest that the antitumorigenic effect of PPARβ/δ activation in endometrial cancer is mediated through the negative regulation of the AKT/GSK3β/β-catenin pathway. These findings warrant further investigation of PPARβ/δ as a therapeutic target in endometrial cancer.

Original languageEnglish (US)
Pages (from-to)358-370
Number of pages13
JournalHormones and Cancer
Volume4
Issue number6
DOIs
StatePublished - Dec 2013

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism
  • Oncology
  • Endocrinology
  • Endocrine and Autonomic Systems
  • Cancer Research

Fingerprint

Dive into the research topics of 'Ligand-Activated Peroxisome Proliferator-Activated Receptor β/δ Modulates Human Endometrial Cancer Cell Survival'. Together they form a unique fingerprint.

Cite this