Differential roles of PPARγ vs TR4 in prostate cancer and metabolic diseases

Abstract

Peroxisome proliferator-activated receptor g (PPARg, NR1C3) and testicular receptor 4 nuclear receptor (TR4, NR2C2) are two members of the nuclear receptor (NR) superfamily that can be activated by several similar ligands/activators including polyunsaturated fatty acid metabolites, such as 13-hydroxyoctadecadienoic acid and 15-hydroxyeicosatetraenoic acid, as well as some anti-diabetic drugs such as thiazolidinediones (TZDs). However, the consequences of the transactivation of these ligands/activators via these two NRs are different, with at least three distinct phenotypes. First, activation of PPARg increases insulin sensitivity yet activation of TR4 decreases insulin sensitivity. Second, PPARg attenuates atherosclerosis but TR4 might increase the risk of atherosclerosis. Third, PPARg suppresses prostate cancer (PCa) development and TR4 suppresses prostate carcinogenesis yet promotes PCa metastasis. Importantly, the deregulation of either PPARg or TR4 in PCa alone might then alter the other receptor's influences on PCa progression. Knocking out PPARg altered the ability of TR4 to promote prostate carcinogenesis and knocking down TR4 also resulted in TZD treatment promoting PCa development, indicating that both PPARg and TR4 might coordinate with each other to regulate PCa initiation, and the loss of either one of them might switch the other one from a tumor suppressor to a tumor promoter. These results indicate that further and detailed studies of both receptors at the same time in the same cells/organs may help us to better dissect their distinct physiological roles and develop better drug(s) with fewer side effects to battle PPARg-and TR4-related diseases including tumor and cardiovascular diseases as well as metabolic disorders.

Fenoxycarb promotes adipogenesis in 3T3‐L1 preadipocytes

“…; Liu et al . ). Recent studies have reported that in addition to their cognate ligands, activities of these receptors could be regulated by a variety of lipophilic molecules, including fatty acids and various environmental chemicals (King‐Jones & Thummel ).…”

TR4 and PPARγ activities are differentially modulated by pyriproxyfen

“…Because both TR4 and PPARγ have high affinities for DR1 elements, target genes of these two receptors are considerably overlapped (Liu et al . ).…”

“…this study, we showed that PPARγ transcriptional activity is significantly stimulated at 400 μM PYR, at which TR4 activity could not be enhanced, clearly showing that TR4 and PPARγ can respond to PYR at different concentrations. Because both TR4 and PPARγ have high affinities for DR1 elements, target genes of these two receptors are considerably overlapped (Liu et al 2014).…”

“…Interestingly, recent studies reported that TR4 also could be activated by PPARγ agonists including PUFAs, their metabolites and rosiglitazone (Liu et al 2007;Tsai et al 2009). In addition, TR4 and PPARγ bind to similar DNA response elements consisting of a direct repeat (DR) AGGTCA core motif sequence with one spacer nucleotide, suggesting that downstream target genes of these two receptors may be considerably overlapped (Liu et al 2014). A similar preference of TR4 and PPARγ for ligands/activators and DNA binding sites prompted us to investigate whether higher concentrations of PYR are able to stimulate PPARγ transcriptional activity.…”

TR4 nuclear receptor enhances the cisplatin chemo-sensitivity via altering the ATF3 expression to better suppress HCC cell growth

“…However, Xie et al [23] found PPAR ligands/activators such as the PUFA metabolites, 15-HETE and 13-HODE, could trans-activate TR4, and some TZDs could also trans-activate TR4 to modulate its down-stream target CD36 activity during foam cell formation/atherosclerosis [39]. …”