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.

Mechanisms of Androgen Receptor Agonist- and Antagonist-Mediated Cellular Senescence in Prostate Cancer

“…It is suggested that PCa progresses from a castration-sensitive PCa (CSPC) to the androgen deprivation therapy (ADT) resistant tumor termed as castration-resistant PCa (CRPC). Both CSPC and CRPC can metastasize leading to the lethal aggressive cancer [4]. Important to note is that the expression of androgen receptor (AR), also in CRPC and metastatic CRPC (mCRPC), is a key factor for tumor proliferation.…”

The Role of Nuclear Receptors in Prostate Cancer

“…In addition, activation of LXRs by their agonists decreased prostate cancer cell proliferation and prostate tumor invasion [59,63,64,65,66,67]. Thus, these data indicate that LXRs play an antioncogenic role in prostate cancer, suggesting that selective LXR modulators could be novel prevention and therapeutic strategies for prostate cancer [68].…”

The Targeted Therapies Era Beyond the Surgical Point of View: What Spine Surgeons Should Know Before Approaching Spinal Metastases

“…73 The mechanisms of resistance generally involve androgen pathways and include the overexpression and/or mutation of the AR, the upregulation of AR coactivators, the activation of AR by tyrosine kinase receptors linking the androgen-regulated pathway with the growth factor signaling pathways and the intratumoral synthesis of active androgens. 68 In Docetaxel-resistant PC, Cabazitaxel showed promising results in terms of OS when compared to Mitoxantrone. 74 Some new options for therapy of metastatic tumor have been specifically targeted to bone lesions, which are the most common PC metastases.…”

“…4,67 Its increasing incidence has been explained not only by improvements in diagnostic methods but also by poorly defined environmental factors; moreover, androgen hormones have a prominent role in the development of PC. 68 Androgen deprivation therapy is indeed the mainstay of treatment, used as first-line approach for patients with advanced and metastatic PC. 69 Blockade of androgen pathways can be obtained with 3 different treatments 70,71 : (1) LHRH ligands, in the form of agonists downregulating LHRH receptors (Goserelin, Leuproline, and Triptorelin) or antagonists such as Abarelix and Degarelix; (2) blockade of androgen synthesis, mostly inhibiting the upregulated enzyme CYP17 with abiraterone or with Ketoconazole; (c) antiandrogens that antagonize the androgen receptor (AR), such as cyproterone acetate, bicalutamide, flutamide, nilutamide, and enzalutamide.…”