Inhibition of testicular embryonal carcinoma cell tumorigenicity by peroxisome proliferator-activated receptor-β/δ- and retinoic acid receptor-dependent mechanisms.

Pei-Li Yao,Frank J Gonzalez,Boo-Hyon Kang,Dylan A Phillips,Tomasz P Dobrzański,Jeffrey M Peters,Bokai Zhu,Li Ping Chen

doi:10.18632/oncotarget.5415

Pei-Li Yao, Frank J Gonzalez + Show 6 more

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https://doi.org/10.18632/oncotarget.5415

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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.

Highlights

Testicular germ cell tumors are prevalent in men 15– 40 years of age with genetic heterogeneity [1]
NTERA-2 cl. D1 (NT2/D1)-MigR1 and NT2/D1hPPARβ/δ cells expressed enhanced green fluorescent protein, while control NT2/D1 cells were devoid of fluorescence (Figure 1A)
Since NT2/D1hPPARβ/δ cells exhibit a relatively high fatty acid binding protein 5 (FABP5):cellular retinoic acid-binding protein II (CRABPII) ratio compared to control NT2/D1 cells (Figure 10), the effect of atRA on invasion and migration was examined to determine if this mechanism modulated the observed phenotype of the model in the present study (Figure 11). These analyses indicated that atRA signaling mediated by retinoic acid receptor (RAR)/retinoid X receptor (RXR) is not dependent on Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) in NT2/D1 cells that exhibit a relatively high FABP5:CRABPII ratio (Figure 10)

Summary

Introduction

Testicular germ cell tumors are prevalent in men 15– 40 years of age with genetic heterogeneity [1]. Embryonal carcinoma is the most common component of mixed testicular germ cell tumors, which are difficult to diagnose, and are highly metastatic [5]. Peroxisome proliferator-activated receptor-β/δ (PPARβ/δ) is a ligand activated transcription factor that actively regulates gene expression through multiple www.impactjournals.com/oncotarget mechanisms [7]. PPARβ/δ and its heterodimerization partner retinoid X receptor (RXR) dynamically bind as a complex to response elements on chromatin after interacting with other proteins such as co-repressors, co-activators, and endogenous agonists [7]. Binding of PPARβ/δ/RXR regulates the expression of a broad range of genes and controls numerous biological processes, including cell differentiation and proliferation, lipid and glucose homeostasis, and inflammation [8]. There are multiple levels of regulation that can impact nuclear receptor-mediated signaling due to competition for the availability of similar co-factors required for an active heterodimerized transcription factor including PPARβ/δ [7, 12,13,14]

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