Endocrine Abstracts

Background: Gonadotropin-releasing hormone (GnRH) receptor is a G protein-coupled receptor involved in the synthesis and release of pituitary gonadotropins. GnRH analogs constitute the most widely employed medical treatment for prostatic cancer. The predominant mechanism of action is presumed to be via the inhibition of gonadotropins and resultant decrease in androgen. Although pituitary and extra-pituitary GnRH-R transcripts appear identical, their functional characteristics may differ and most extra-pituitary GnRH-Rs may not discriminate between agonists and antagonists in the same way as do pituitary GnRH-Rs. However, GnRH analogs have also been shown to directly inhibit prostate cancer cells both in vitro and in vivo. GnRH analogues influence the in vitro proliferation of cultured human cells by complex interactions that are still partially understood.

Aims: Our hypothesis is that GnRH analogues modulate prostate cancer progression acting on invasive capacity and androgen responsiveness of tumor cells. So, GnRH triggering may revert maligancy of advanced castrated refractory prostate cancer models.

Results: We demonstrated that: GnRH analogues show non pituitary effects both in hormone sensitive and castrated refractory prostate cancer cell models. GnRH analogues induce antiproliferative and pro-apoptotic effects altering the p75NTR:TrkA and p75NTR/TrkB ratios, activating extrinsic apoptotic pathways and partecipating to reduce anoikis and survival in the blood stream and in metastatic sites. In particular, GnRH analogues induce PTEN expression and reduce Akt actity in PTEN+/AR+22rv1 cells and induce extrinsic apoptosis pathways triggering TRAIL-Receptor signaling. GnRH analogues revert malignant phenotype by induction of p75 NTR and AR expression both in AR positive (22rv1 and LAPC-4) and negative (PC3) cell models resulting synergistic with bicalutamide and Radiotherapy both in vitro and in vivo.

Conclusions: Our results support a potential use of these agents for the treatment of locally aggressive as well as advanced prostate cancer.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This research did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.