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.

Keywords: AR; GnRH; GnRH-R; androgen receptors; androgens; castration-resistant prostate cancer; gonadotropin-releasing hormone; gonadotropin-releasing hormone receptors.

Figure 1

Most frequent mutations of AR detected in tissues and plasma cfDNA from CRPC patients. Upper part, representation of the AR gene structure. Lower part, representation of the AR protein structure with the most frequently mutated amino acids. T878A, alanine substituted by threonine; H875Y, tyrosine substituted by histidine; W742C, cysteine substituted by triptophan; F876L, leucine substituted by phenylalanine. Abbreviations: AR, androgen receptor; NTD, NH₂-terminal transactivation domain; DBD, DNA-binding domain; LBD, ligand-binding domain.

Figure 2

Molecular mechanisms involved in the persistent activity of the androgen/AR axis in CRPC cells. The persistent activation of the androgen/AR axis has been attributed to several mechanisms, including: (1) intratumoral synthesis of androgens; (2) AR amplification; (3) AR mutations and alternative splicing; and (4) increased expression/activity of transcription factors and coregulators of the AR. Abbreviations: AR, androgen receptor.

Figure 3

Intracellular signaling pathways involved in the antitumor activity of the GnRH-R in CRPC cells. The binding of GnRH analogs (both agonists and antagonists) to locally expressed GnRH-Rs triggers the activation of the Gαi/cAMP pathway. By decreasing cAMP levels, GnRH-R ligands activate the MAPK kinase cascades (i.e., p38MAPK and JNK), deeply involved in their anticancer effects. GnRH-R analogs also trigger the activation of a PTP, an enzyme responsible for the dephosphorylation (i.e., inactivation) of growth factor receptors (RTK), thus leading to the suppression of the expression/activity of their intracellular signaling mediators (i.e., ERK1/2 and AKT). In addition, AKT inhibition also leads to the stimulation of the JNK signaling pathway, further potentiating its antitumor activity. Abbreviations: cAMP, cyclic adenosine monophosphate; p38, p38 mitogen-activated protein kinase; JNK, c-Jun N-terminal kinase; RTK, receptor tyrosine kinase; AKT, protein kinase B; ERK1/2, extracellular signal-regulated kinase 1/2.