The emerging roles of orphan nuclear receptors in prostate cancer

Abstract

Orphan nuclear receptors are members of the nuclear receptor (NR) superfamily and are so named because their endogenous physiological ligands are either unknown or may not exist. Because of their important regulatory roles in many key physiological processes, dysregulation of signalings controlled by these receptors is associated with many diseases including cancer. Over years, studies of orphan NRs have become an area of great interest because their specific physiological and pathological roles have not been well-defined, and some of them are promising drug targets for diseases. The recently identified synthetic small molecule ligands, acting as agonists or antagonists, to these orphan NRs not only help to understand better their functional roles but also highlight that the signalings mediated by these ligand-independent NRs in diseases could be therapeutically intervened. This review is a summary of the recent advances in elucidating the emerging functional roles of orphan NRs in cancers, especially prostate cancer. In particular, some orphan NRs, RORγ, TR2, TR4, COUP-IFII, ERRα, DAX1 and SHP, exhibit crosstalk or interference with androgen receptor (AR) signaling in either normal or malignant prostatic cells, highlighting their involvement in prostate cancer progression as androgen and AR signaling pathway play critical roles in this process. We also propose that a better understanding of the mechanism of actions of these orphan NRs in prostate gland or prostate cancer could help to evaluate their potential value as therapeutic targets for prostate cancer.

Mechanistic insight into nuclear receptor‐mediated regulation of bile acid metabolism and lipid homeostasis by grape seed procyanidin extract (GSPE)

“…These receptors can either bind directly to their specific REs as monomers, which bind to a single half site, or in conjunction with RXR as a heterodimer . The orphan receptor family includes chicken ovalbumin upstream promoter transcription factor 2 (COUP‐TFII), estrogen‐related receptor alpha (ERRα), dosage‐sensitive sex reversal, adrenal hypoplasia critical region, on chromosome X, gene 1 (DAX1), and Retinoic Acid Receptor (RAR)‐related orphan receptor gamma (RORγ) . Because of their critical regulatory roles in many key physiological processes, dysregulation of important signaling pathways controlled by these receptors is associated with many diseases, including cancer .…”

“…17 Because of their critical regulatory roles in many key physiological processes, dysregulation of important signaling pathways controlled by these receptors is associated with many diseases, including cancer. 17 In addition, evidence suggests that orphan NRs play essential roles in the innate immune response and help to prevent pathogenic inflammatory responses and enhance antimicrobial host defense. 18 It has been suggested that identification of new functions for the orphan NRs could facilitate development of novel preventive and therapeutic strategies against human inflammatory diseases (reviewed in the work of Jin et al 18 ).…”

Estrogen-Related Receptor Alpha: An Under-Appreciated Potential Target for the Treatment of Metabolic Diseases

“…Similarly, increasing the expression of peroxisome proliferator-activated receptor gamma coactivator 1 alpha (PPARGC1A), the protein ligand of ESRRA, increases energy expenditure and reduces obesity [23]. So far, most previous studies of ESRR actions have focused on its role in cancer progression and this topic has been reviewed elsewhere [24][25][26][27][28][29][30][31][32][33][34][35]. There have also been a few studies on its roles in bone and muscle differentiation [36][37][38], trauma/shock [39], and infection [40].…”

WOMEN IN CANCER THEMATIC REVIEW: New roles for nuclear receptors in prostate cancer

“…TLX has been reported to have a role in overcoming senescence (oncogene induced and PTEN-loss induced) in multiple tumour types including prostate, as it can repress p21 and activate SIRT1, both of which are prominent senescence-related genes (Wu et al 2015). This role in senescence may make TLX an important factor in cancer progression and CRPC, where senescence is thought to be a vital part of tumour resistance to treatment and recurrence, and Wu and coworkers suggest that TLX may promote the self-renewal and maintenance of cancer stem cells (Wu et al 2016a). Further research into the role of TLX in prostate cancer progression is clearly needed, especially as in our analysis of TCGA data (Fig.…”

“…This, however, does not preclude the possibility of modifying their activity using synthetic compounds and small molecules, and so they are potential drug targets in cancer and other diseases. A recent review has covered orphan receptors in prostate cancer in detail (Wu et al 2016a), so here we will focus on a small number of prominent receptors, which were identified as highly altered in our TCGA analysis.…”