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 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.
Division of Reproductive Biology Research, Department of Obstetrics and Gynecology, Feinberg School of Medicine, Northwestern University, 250 E. Superior Street, Suite 3-2306, Chicago, IL, 60611-02914, USA.
J J
JJ
Ma
D
D
Monsivais
M T
MT
Dyson
J S
JS
Coon
S
S
Malpani
M
M
Ono
H
H
Zhao
H
H
Xin
M E
ME
Pavone
J J
JJ
Kim
D
D
Chakravarti
S E
SE
Bulun
D017209:Apoptosis / Q000187:drug effects / Q000235:genetics; D002277:Carcinoma / Q000188:drug therapy* / Q000473:pathology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics; D016889:Endometrial Neoplasms / Q000188:drug therapy* / Q000473:pathology; D005260:Female; D038362:Glycogen Synthase Kinase 3 / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006801:Humans; D058990:Molecular Targeted Therapy; D047492:Peroxisome Proliferator-Activated Receptors / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D015398:Signal Transduction / Q000187:drug effects; D013844:Thiazoles / Q000494:pharmacology; D051176:beta Catenin / Q000378:metabolism; D010636:Phenols; D013438:Sulfhydryl Compounds
D038362:Glycogen Synthase Kinase 3; D000071679:Glycogen Synthase Kinase 3 beta; D047492:Peroxisome Proliferator-Activated Receptors; D051057:Proto-Oncogene Proteins c-akt; D034741:RNA, Small Interfering; D013844:Thiazoles; D051176:beta Catenin; C425931:GW 501516; C479979:(4-(((2-(3-fluoro-4-(trifluoromethyl)phenyl)-4-methyl-1,3-thiazol-5-yl)methyl)sulfanyl)-2-methylphenoxy)acetic acid; D010636:Phenols; D013438:Sulfhydryl Compounds; C000605506:GSK3B protein, human