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

2015-02-09 00:01:10

Oncoscience; 9 February 2015 ; Online ISSN: 2331-4737



Shin-Jen Lin, Dong-Rong Yang, Nancy Wang, Ming Jiang, Hiroshi Miyamoto, Gonghui Li, Chawnshang Chang



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.



Introduction



Testicular nuclear receptor 4 (TR4) belongs to the nuclear receptor superfamily and was first cloned in 1994. TR4 physiological functions are involved in metabolism, cancer development, fertility, bone diseases, cardiovascular diseases, etc. Peroxisome proliferator-activated receptor gamma (PPARG), another nuclear receptor, also has multiple functions mostly in metabolism, cancer development, cardiovascular diseases, bone diseases, etc.



TR4 and PPARG share many similarities yet also have distinct functions in some selective diseases. First, both TR4 and PPARG genes were located in the chromosome 3p at regions 3p24 and 3p25, respectively. Second, they share the same ligands/activators, i.e. polyunsaturated fatty acids and thiazolidinediones (TZDs), which transactivate their downstream target genes. Third, they bind to the similar Hormone-Response-Elements (HREs) sequences, i.e. two consecutive AGGTCA sequences with spacing of 0-5 nucleotides (direct repeat 0-5). However, more and more evidences indicate that these 2 nuclear receptors can also function oppositely in some selective diseases. First, they exert differential effects on insulin sensitivity with PPARG increasing insulin sensitivity vs
TR4 decreasing insulin sensitivity. Second, PPARG suppresses atherosclerosis while TR4 enhances atherosclerosis. Third, PPARG increases osteoporosis while TR4 decreases osteoporosis. These contrasting results suggest that TR4 and PPARG may act as competitors for their upstream ligands and/or their downstream target gene modulation.



Lin et al recently reported that TR4 played a protective role in PCa initiation via modulation of the DNA damage/repair pathway. They showed TR4 could suppress PCa development in 3 different mouse models and 2 different cell lines. Interestingly, Jiang et al also reported similar results showing knocking-out PPARG resulted in enhanced prostatic intraepithelial neoplasia (PIN) in the mouse model. Here we report that TR4 can enhance or suppress PCa initiation depending on the availability of PPARG.



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Key Words



Prostate cancer | TR4 | PPARG