New Insights in Prostate Cancer Development and Tumor Therapy: Modulation of Nuclear Receptors and the Specific Role of Liver X Receptors

Abstract

Prostate cancer (PCa) incidence has been dramatically increasing these last years in westernized countries. Though localized PCa is usually treated by radical prostatectomy, androgen deprivation therapy is preferred in locally advanced disease in combination with chemotherapy. Unfortunately, PCa goes into a castration-resistant state in the vast majority of the cases, leading to questions about the molecular mechanisms involving the steroids and their respective nuclear receptors in this relapse. Interestingly, liver X receptors (LXRα/NR1H3 and LXRβ/NR1H2) have emerged as new actors in prostate physiology, beyond their historical roles of cholesterol sensors. More importantly LXRs have been proposed to be good pharmacological targets in PCa. This rational has been based on numerous experiments performed in PCa cell lines and genetic animal models pointing out that using selective liver X receptor modulators (SLiMs) could actually be a good complementary therapy in patients with a castration resistant PCa. Hence, this review is focused on the interaction among the androgen receptors (AR/NR3C4), estrogen receptors (ERα/NR3A1 and ERβ/NR3A2), and LXRs in prostate homeostasis and their putative pharmacological modulations in parallel to the patients' support.

Keywords: LXRs; androgens; cholesterol; estrogens; metastasis; oxysterols; prostate cancer; signaling pathway.

Figure 1

Schematic structure and functioning of steroid receptors. Nuclear receptors are composed of an N-terminal domain (NTD), a DNA-binding domain (DBD) responsible of the binding to the DNA-target sequences usually located within the promoters of the targets genes and a C-terminal ligand-binding domain (LBD), which is specific to the molecule. Canonically, it is admitted that steroid receptors are located within the cytoplasm in the absence of hormone, bound to heat shock proteins (HSP) that impede shuttling to the nucleus. The binding of the steroid (L) allows the chaperones to unbind from the receptor and migrate to the nucleus after a homodimerization. The binding of co-activators (Coact.) makes the recruitment of the transcriptional machinery possible, along with the RNA polymerase II (RNA Pol II), the transcription of the target gene, and the physiological effects.

Figure 2

Schematic structure and functioning of nuclear receptors bound as heterodimers with retinoid X receptors (RXR). The non-steroid nuclear receptor (grey) is supposed to be bound with RXRs, a receptor for 9-cis retinoic acid (deep purple), to the DNA. In absence of ligand, the transcriptional activity is blocked (thin green arrow) by co-repressors (Corep.). As for the steroid receptors, the binding of co-activators (Coact.) makes possible the recruitment of the transcriptional machinery, along with the RNA polymerase II (RNA Pol II), the transcription of the target gene (thick green arrow), and the physiological effects.

Figure 3

Summary of the various treatments proposed to treat PCa. A focus is made on some nuclear receptors. The androgen (AR) and estrogen receptor (ER) α have deleterious effects on prostate cancer (PCa) progression when activated by their respective ligands dihydrotestosterone (DHT) and 17β-estradiol (E2). Conversely, nuclear oxysterol receptors (LXRα/β) and ERβ block the progression of PCa in animal models when activated by their respective ligands. As indicated, AR and ERα activity in PCa could be modulated by LXRs, directly or indirectly. For more details see the text. DDA: dendrogenin A.