Background: PCa stem/progenitor cells develop higher chemoresistance. Results: High TR4 levels in PCa stem/progenitor cells were shown to be critical in conferring chemoresistance to these cells. Conclusion: TR4-Oct4-IL1Ra signaling is important in conferring chemoresistance to PCa stem/progenitor cells. Significance: This finding suggests that targeting TR4 and its downstream molecules may be a better therapeutic approach to battle PCa stem/progenitor cell-originated chemoresistance.

Testicular nuclear receptor 4 (TR4) plays protective roles against oxidative stress and DNA damage and might contribute to aging. Our recent clinical tumor tissue staining results showed higher expression of TR4 in prostate cancer (PCa) patients with high Gleason scores compared to the tissues with the low Gleason scores. In vitro migration/invasion assays after manipulation of the TR4 expression in PCa cells showed that TR4 promoted PCa cells migration/invasion. Mechanism dissection found that the CCL2/CCR2 signal plays the key role in the mediation of TR4-promoted PCa cells migration/invasion. Chromatin immunoprecipitation and Luciferase assays further confirmed TR4 modulation of CCL2 at the transcriptional level and addition of the CCR2 antagonist led to interruption of the TR4-enhanced PCa cells migration/ invasion. Finally, the orthotopic xenografted mice studies using the luciferase expressing CWR22Rv1 cells found that TR4 enhanced PCa metastasis and this increased metastasis was reversed when the CCR2 antagonist was injected into the mice. Together, these in vitro and in vivo results revealed a positive role of TR4 in PCa metastasis and demonstrated CCL2/CCR2 signaling as an important mediator in exerting TR4 action. This finding suggests that TR4 may represent a biomarker related to PCa metastasis and targeting the TR4-CCL2/CCR2 axis may become a new therapeutic approach to battle PCa metastasis.Prostate cancer (PCa) is the second leading cause of cancer related deaths among men in the United States. Since PCa cells depend on androgen/androgen receptor (AR) signaling for their growth, 1 the androgen deprivation therapy (ADT), through either chemical or surgical castration, has been an effective therapy that leads to a regression of androgendependent PCa.2 However, almost all patients eventually relapse with recurrent (castration resistant) PCa and metastases, which respond to few treatments. In this study, we investigated the TR4 role in PCa metastasis using in vitro migration/invasion assays and in vivo metastasis mouse model and demonstrated the positive role of TR4 in promoting PCa metastasis. The mechanism dissection studies further proved that TR4 might function via modulation of the CCL2/CCR2 signaling.

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Testicular nuclear receptor 4 (TR4), also known as NR2C2, belongs to the nuclear receptor superfamily and shares high homology with the testicular nuclear receptor 2. The natural ligands of TR4 remained unclear until the recent discoveries of several energy/lipid sensors including the polyunsaturated fatty acid metabolites, 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, and their synthetic ligands, thiazolidinediones, used for treatment of diabetes. TR4 is widely expressed throughout the body and particularly concentrated in the testis, prostate, cerebellum, and hippocampus. It has been shown to play important roles in cerebellar development, forebrain myelination, folliculogenesis, gluconeogenesis, lipogenesis, muscle development, bone development, and prostate cancer progression. Here we provide a comprehensive summary of TR4 signaling including its upstream ligands/activators/suppressors, transcriptional coactivators/repressors, downstream targets, and their in vivo functions with potential impacts on TR4-related diseases. Importantly, TR4 shares similar ligands/activators with another key nuclear receptor, peroxisome proliferator-activated receptor γ, which raised several interesting questions about how these 2 nuclear receptors may collaborate with or counteract each other's function in their related diseases. Clear dissection of such molecular mechanisms and their differential roles in various diseases may help researchers to design new potential drugs with better efficacy and fewer side effects to battle TR4 and peroxisome proliferator-activated receptor γ involved diseases.

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