Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms
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Pei-Li Yao1, Li Ping Chen1, Tomasz P. Dobrzański1, Dylan A. Phillips1, Bokai Zhu1, Boo-Hyon Kang2, Frank J. Gonzalez3, Jeffrey M. Peters1
1Department of Veterinary and Biomedical Sciences, The Center of Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, Pennsylvania, USA
2Chemon Nonclinical Research Institute, Nampyeong-ro, Yangji-myeon, Cheoin-gu, Yongin-si, Gyeonggi-do, Korea
3Laboratory of Metabolism, National Cancer Institute, Bethesda, Maryland, USA
Jeffrey M. Peters, e-mail: [email protected]
Pei-Li Yao, e-mail: [email protected]
Keywords: peroxisome proliferator-activated receptor-β/δ, testicular embryonal carcinoma, retinoic acid receptor, matrix metalloproteinase-2, tumorigenicity
Received: July 06, 2015 Accepted: September 15, 2015 Published: September 26, 2015
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.
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