title: Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.
abstract: Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) has important physiological functions in control of cell growth, lipid and glucose homeostasis, differentiation and inflammation. To investigate the role of PPARβ/δ in cancer, stable human testicular embryonal carcinoma cell lines were developed that constitutively express PPARβ/δ. Expression of PPARβ/δ caused enhanced activation of the receptor, and this significantly decreased proliferation, migration, invasion, anchorage-independent growth, and also reduced tumor mass and volume of ectopic xenografts derived from NT2/D1 cells compared to controls. The changes observed in xenografts were associated with decreased PPARβ/δ-dependent expression of proliferating cell nuclear antigen and octamer-binding transcription factor-3/4, suggesting suppressed tumor proliferation and induction of differentiation. Inhibition of migration and invasion was mediated by PPARβ/δ competing with formation of the retinoic acid receptor (RAR)/retinoid X receptor (RXR) complex, resulting in attenuation of RARα-dependent matrix metalloproteinase-2 expression and activity. These results demonstrate that PPARβ/δ mediates attenuation of human testicular embryonal carcinoma cell progression through a novel RAR-dependent mechanism and suggest that activation of PPARβ/δ inhibits RAR/RXR dimerization and represents a new therapeutic strategy.
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Pei-Li
authors.initials: PL
authors.lastname: Yao
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Li Ping
authors.initials: LP
authors.lastname: Chen
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Tomasz P
authors.initials: TP
authors.lastname: Dobrzański
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Dylan A
authors.initials: DA
authors.lastname: Phillips
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Bokai
authors.initials: B
authors.lastname: Zhu
authors.affiliation: Chemon Nonclinical Research Institute, Nampyeong-ro, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do, Korea.
authors.forename: Boo-Hyon
authors.initials: BH
authors.lastname: Kang
authors.affiliation: Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, USA.
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.affiliation: Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA.
authors.forename: Jeffrey M
authors.initials: JM
authors.lastname: Peters
mesh_terms: D000293:Adolescent; D000328:Adult; D063646:Carcinogenesis; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000502:physiology; D006801:Humans; D008297:Male; D047494:PPAR delta / Q000378:metabolism*; D018168:Receptors, Retinoic Acid / Q000378:metabolism*; D013736:Testicular Neoplasms / Q000378:metabolism* / Q000473:pathology*; D055815:Young Adult
chemical_list: D047494:PPAR delta; D018168:Receptors, Retinoic Acid
keywords: matrix metalloproteinase-2; peroxisome proliferator-activated receptor-β/δ; retinoic acid receptor; testicular embryonal carcinoma; tumorigenicity