Gonadotropin-Releasing Hormone Receptors in Prostate Cancer: Molecular Aspects and Biological Functions.

Abstract

Pituitary Gonadotropin-Releasing Hormone receptors (GnRH-R) mediate the activity of the hypothalamic decapeptide GnRH, thus playing a key role in the regulation of the reproductive axis. Early-stage prostate cancer (PCa) is dependent on serum androgen levels, and androgen-deprivation therapy (ADT), based on GnRH agonists and antagonists, represents the standard therapeutic approach for PCa patients. Unfortunately, the tumor often progresses towards the more aggressive castration-resistant prostate cancer (CRPC) stage. GnRH receptors are also expressed in CRPC tissues, where their binding to both GnRH agonists and antagonists is associated with significant antiproliferative/proapoptotic, antimetastatic and antiangiogenic effects, mediated by the Gαi/cAMP signaling cascade. GnRH agonists and antagonists are now considered as an effective therapeutic strategy for CRPC patients with many clinical trials demonstrating that the combined use of these drugs with standard therapies (i.e., docetaxel, enzalutamide, abiraterone) significantly improves disease-free survival. In this context, GnRH-based bioconjugates (cytotoxic drugs covalently linked to a GnRH-based decapeptide) have been recently developed. The rationale of this treatment is that the GnRH peptide selectively binds to its receptors, delivering the cytotoxic drug to CRPC cells while sparing nontumor cells. Some of these compounds have already entered clinical trials.

• Authors: Fabrizio Fontana, Monica Marzagalli, Marina Montagnani Marelli, Michela Raimondi, Roberta M Moretti, Patrizia Limonta
• Journal: International journal of molecular sciences (Int J Mol Sci) Vol. 21 Issue 24 (Dec 14 2020) ISSN: 1422-0067 [Electronic] Switzerland
• PMID: 33327545 (Publication Type: Journal Article, Review)

Chemical References

• Androstenes
• Benzamides
• Nitriles
• Receptors, LHRH
• Docetaxel
• Phenylthiohydantoin
• Gonadotropin-Releasing Hormone
• enzalutamide
• abiraterone

Topics

• Androstenes (therapeutic use)
• Animals
• Benzamides
• Docetaxel (therapeutic use)
• Gonadotropin-Releasing Hormone (metabolism)
• Humans
• Male
• Nitriles
• Phenylthiohydantoin (analogs & derivatives, therapeutic use)
• Prostatic Neoplasms (drug therapy, metabolism)
• Prostatic Neoplasms, Castration-Resistant (drug therapy, metabolism)
• Receptors, LHRH (metabolism)
• Signal Transduction (drug effects)