Dissecting the Hormonal Signaling Landscape in Castration-Resistant Prostate Cancer

Abstract

Understanding the molecular mechanisms underlying prostate cancer (PCa) progression towards its most aggressive, castration-resistant (CRPC) stage is urgently needed to improve the therapeutic options for this almost incurable pathology. Interestingly, CRPC is known to be characterized by a peculiar hormonal landscape. It is now well established that the androgen/androgen receptor (AR) axis is still active in CRPC cells. The persistent activity of this axis in PCa progression has been shown to be related to different mechanisms, such as intratumoral androgen synthesis, AR amplification and mutations, AR mRNA alternative splicing, increased expression/activity of AR-related transcription factors and coregulators. The hypothalamic gonadotropin-releasing hormone (GnRH), by binding to its specific receptors (GnRH-Rs) at the pituitary level, plays a pivotal role in the regulation of the reproductive functions. GnRH and GnRH-R are also expressed in different types of tumors, including PCa. Specifically, it has been demonstrated that, in CRPC cells, the activation of GnRH-Rs is associated with a significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic activity. This antitumor activity is mainly mediated by the GnRH-R-associated Gαi/cAMP signaling pathway. In this review, we dissect the molecular mechanisms underlying the role of the androgen/AR and GnRH/GnRH-R axes in CRPC progression and the possible therapeutic implications.

A Small Peptide Targeting the Ligand-Induced Androgen Receptor/Filamin a Interaction Inhibits the Invasive Phenotype of Prostate Cancer Cells

“…At early stages the management protocol of patients is represented by surgery or radiotherapy, which fail in 10–20% of cases. Later, recurrent patients are subjected to androgen deprivation therapy (ADT), whose efficacy is time-limited so that most patients develop castration-resistant prostate cancer (CRPC) [ 21 , 22 ]. This is a multifaced type of cancer, in which often cells still depend on AR for migrating or growing in presence of very low levels of circulating androgens [ 23 ].…”

Advances in the Current Understanding of the Mechanisms Governing the Acquisition of Castration-Resistant Prostate Cancer

“…The ARV-567es is a common AR-V that lacks LBD exons 5–7, while retaining the hinge region encoded by exon 4 that is involved in the receptor nuclear localization [ 86 , 94 , 95 , 96 ]. In contrast to AR-V7, this variant has only been detected in cases of advanced or malignant PCA, including CRPC [ 87 , 94 , 97 , 98 ].…”

Inhibition of Scavenger Receptor Class B Type 1 (SR-B1) Expression and Activity as a Potential Novel Target to Disrupt Cholesterol Availability in Castration-Resistant Prostate Cancer

“…Androgen receptor (AR) activity is the primary driver of PCa, and its activation persists in the vast majority of CRPC, in part, due to intratumoral androgen synthesis [ 8 , 9 , 10 , 11 ]. The recognition that AR signaling remains integral to CRPC drove the development of second-generation AR targeted agents (ARTAs), namely, potent AR ligand-binding antagonists [ 12 , 13 ] and inhibitors of the key enzyme in steroid synthesis from cholesterol precursor, cytochrome P450 isoform 17A1 (CYP17A1) [ 14 , 15 ], that are now routinely used to manage CRPC prior to, or in conjunction with, chemotherapy [ 16 , 17 ].…”