TR4 Nuclear Receptor Different Roles in Prostate Cancer Progression

Shin-Jen Lin,Gonghui Li,Dong-Rong Yang,Chawnshang Chang

doi:10.3389/fendo.2015.00078

Abstract

Nuclear receptors are important to maintain the tissue homeostasis. Each receptor is tightly controlled and under a very complicated balance. In this review, we summarize the current findings regarding the nuclear receptor TR4 and its role in prostate cancer (PCa) progression. In general, TR4 can inhibit the PCa carcinogenesis. However, when PPARγ is knocked out, activation of TR4 can have an opposite effect to promote the PCa carcinogenesis. Clinical data also indicates that higher TR4 expression is found in PCa tissues with high Gleason scores compared to those tissues with low Gleason scores. In vitro and in vivo studies show that TR4 can promote PCa progression. Mechanism dissection indicates that TR4 inhibits PCa carcinogenesis through regulating the tumor suppressor ATM to reduce DNA damages. On the other hand, in the absence of PPARγ, TR4 tends to increase the stem cell population and epithelial–mesenchymal transition (EMT) via regulating CCL2, Oct4, EZH2, and miRNA-373-3p expression that results in increased PCa carcinogenesis. In opposition to PCa initiation, TR4 can increase PCa metastasis via modulating the CCL2 signals. Finally, targeting TR4 enhances the chemotherapy and radiation therapy sensitivity in PCa. Together, these data suggest TR4 is a key player to control PCa progression, and targeting TR4 with small molecules may provide us a new and better therapy to suppress PCa progression.

Highlights

The testicular nuclear receptor 4 (TR4) was first cloned in 1994, and was identified as one of critical nuclear receptors to maintain the physiological homeostasis [1]
The results suggest that TZD treatment may have different effects on prostate cancer (PCa) progression that depends on the TR4 expression status
Yang et al found 38% of bladder cancer patients have a PPARγ gene amplification, which indicates the unbalance between TR4 and PPARγ plays an important role in both PCa and bladder cancer [21]

Summary

Introduction

The testicular nuclear receptor 4 (TR4) was first cloned in 1994, and was identified as one of critical nuclear receptors to maintain the physiological homeostasis [1]. At 14 weeks, much smaller PCa masses were seen in the mice injected with TR4 knocked-down cells These in vivo results confirmed the in vitro data showing overexpressing TR4 could lead to PCa tumor growth in mPrE-/- cells xenografts [18]. TZD treatment decreased colony formation on CWR22RV1 cells transfected with scramble shRNA compared to vehicle control They confirmed these different in vitro phenotypes using another PCa cell line, C4-2, and obtained similar results [20]. TZD treatment had no effect on CWR22RV1_scr invasion compared to vehicle control They confirmed these different in vitro phenotypes using C4-2 cells, and obtained similar results [20]. The results conclude that TZD treatment has adverse effects on PCa progression in vivo when TR4 is low, and suggests treating those diabetic PCa patients who lost one allele of TR4 with TZD may lead to PCa progression

TZD Has Different Effects on HRAS Expression

HRAS Specific Inhibitor Interrupts TZD Induced Cell Migration and Invasion

Findings

Conclusion