TR4 nuclear receptor enhances prostate cancer initiation via altering the stem cell population and EMT signals in the PPARG-deleted prostate cells

Abstract

A recent report indicated that the TR4 nuclear receptor might suppress the prostate cancer (PCa) initiation via modulating the DNA damage/repair system. Knocking-out peroxisome proliferator-activated receptor gamma (PPARG), a nuclear receptor that shares similar ligands/activators with TR4, promoted PCa initiation. Here we found 9% of PCa patients have one allele of PPARG deletion. Results from in vitro cell lines and in vivo mouse model indicated that during PCa initiation TR4 roles might switch from suppressor to enhancer in prostate cells when PPARG was deleted or suppressed (by antagonist GW9662). Mechanism dissection found targeting TR4 in the absence of PPARG might alter the stem cell population and epithelial-mesenchymal transition (EMT) signals. Together, these results suggest that whether TR4 can enhance or suppress PCa initiation may depend on the availability of PPARG and future potential therapy via targeting PPARG to battle PPARG-related diseases may need to consider the potential side effects of TR4 switched roles during the PCa initiation.

TR4 Nuclear Receptor Different Roles in Prostate Cancer Progression

“…Using cell transformation with colony formation assays, they found knocking-down TR4 suppressed, while overexpression of TR4 promoted PCa carcinogenesis in mPrE -/- cells, which is also opposite from the mPrE +/+ cells data ( 17 ). Together, results support the above findings that different TR4 effects on prostate epithelium cell proliferation and PCa initiation are dependent on the deletion status of PPAR γ ( 17 , 18 ).…”

“…In contrast, at 14 weeks, much smaller PCa masses were seen in the mice injected with TR4 knocked-down cells. These in vivo results therefore confirmed the in vitro data showing overexpressing TR4 could lead to PCa tumor growth in mPrE -/- cells xenografts ( 18 ).…”

“…The results showed knocking down TR4 in mPrE +/+ cells treated with GW9662 suppressed cell proliferation, which is consistent with the mPrE -/- cell data above. Together, the results confirm the above conclusion that TR4 may exert different effects on prostate cell proliferation depending on the PPARγ status that either was deleted or suppressed by its antagonists ( 18 ).…”

“…Lin et al analyzed Peroxisome Proliferator-Activated receptor gamma (PPAR γ) gene deletion in 69 human PCa samples with fluorescent in situ hybridization (FISH) assays, and results showed 9% of PCa samples have one allele PPAR γ deletion. In contrast, there was no PPAR γ deletion in their normal prostate compartment (Fisher’s test, p = 0.0279), suggested the deletion of PPAR γ may have some linkage to the PCa initiation ( 18 ).…”

“…In contrast, knocking-down TR4 failed to show such prostate de-differentiation in mPrE -/- cells, suggesting TR4 might regulate PCa growth in the absence of PPARγ by mediating PCa to a more poorly differentiated type of cancer. Molecular mechanism dissection found overexpressing TR4 in mPrE -/- cells enhanced the expression of CD44 and Scal1, but eliminated the expression of E-cadherin, indicating an epithelial–mesenchymal transition (EMT) in the stem cell-like population among PCa cells ( 18 ).…”