Differential signaling of the GnRH receptor in pituitary gonadotrope cell lines and prostate cancer cell lines

Abstract

The GnRH receptor (GnRHR) mediates the pituitary functions of GnRH, as well as its anti-proliferative effects in sex hormone-dependent cancer cells. Here we compare the signaling of GnRHR in pituitary gonadotrope cell lines vs. prostate cancer cell lines. We first noticed that the expression level of PKCα, PKCβII and PKCε is much higher in αT3-1 and LβT2 gonadotrope cell lines vs. LNCaP and DU-145 cell lines, while the opposite is seen for PKCδ. Activation of PKCα, PKCβII and PKCε by GnRH is relatively transient in αT3-1 and LβT2 gonadotrope cell lines and more prolonged in LNCaP and DU-145 cell lines. On the otherhand, the activation and re-distribution of the above PKCs by PMA was similar for both gonadotrope cell lines and prostate cancer cell lines. Activation of ERK1/2 by GnRH and PMA was robust in the gonadotrope cell lines, with a smaller effect observed in the prostate cancer cell lines. The Ca2+ ionophore A23187 stimulated ERK1/2 in gonadotrope cell lines but not in prostate cancer cell lines. GnRH, PMA and A23187 stimulated JNK activity in gonadotrope cell lines, with a more sustained effect in prostate cancer cell lines. Sustained activation of p38 was observed for PMA and A23187 in Du-145 cells, while p38 activation by GnRH, PMA and A23187 in LβT2 cells was transient. Thus, differential expression and re-distribution of PKCs by GnRH and the transient vs. the more sustained nature of the activation of the PKC-MAPK cascade by GnRH in gonadotrope cell lines vs. prostate cancer cell lines respectively, may provide the mechanistic basis for the cell context-dependent differential biological responses observed in GnRH interaction with pituitary gonadotropes vs. prostate cancer cells.

In Search of the Molecular Mechanisms Mediating the Inhibitory Effect of the GnRH Antagonist Degarelix on Human Prostate Cell Growth

“…Interestingly, we found a few genes affected at 6 and 24h, and instead, we identified that the biological processes related to cell adhesion, the cell cycle, and transcription were affected at 24h. GnRHR is known to be a Gi-coupled protein, and it is also possible that cross-talks with the growth factor receptors resulted in protein and lipid changes that altered the growth rate of BPH-1 cells [ 41 , 42 , 54 , 55 ]. Specifically, the gene-grouping analysis showed that, in addition to affecting the G-couple receptor related genes, degarelix-deregulated gene clusters, which included blood vessel development, apoptosis, cell proliferation, inflammation, and EGF-like genes.…”

“…Also, degarelix could deregulate MAPK directly through GnRHR or indirectly through the counteraction of growth factors and hormones present on BPH. Each MAPK cascade is activated by a specific stimulus, although a cross-talk between GnRH and growth factor signaling is also possible [ 41 , 42 , 54 , 55 ]. Complementary, steroidogenic, and cancerous tissues highly express translocator protein (TSPO), and its expression can be controlled by the following pathway component: PKC-MEK-ERK [ 63 ].…”

Discovery of Novel Non-Steroidal Cytochrome P450 17A1 Inhibitors as Potential Prostate Cancer Agents

“…The link between the disease and the production of male hormones has been established since 1941 and treatments aimed at blocking the synthesis of these hormones, so called androgen deprivation therapies (ADT), were subsequently developed for clinical use [ 2 ]. A notable example involves usage of gonadotropin releasing hormone (GnRH) agonists and antagonists to reduce serum testosterone levels known as “chemical castration” [ 3 ]. Unfortunately, resistance to ADT occurs within a short period of time and PCa evolves into castration resistant prostate cancer (CRPC), in which the cancer cells produce androgens via de novo and “back door” pathways [ 4 , 5 ].…”

The gonadotropin-releasing hormone system: Perspectives from reproduction to cancer (Review)

“…Initially, it was described that in tumor cells the hGnRHR was exclusively coupled to Gi and consequently inhibit the cAMP accumulation, this action presumably mediates the anti-proliferative effect in these cells (61,67,68). some reports, however, indicated that for tumor cells the hGnRHR is able to activate several G-proteins in a specific cell background (69). The evidence so far indicates that the anti-proliferative response induced by hGnRHR activation results in apoptosis and G2/M arrest in the cell cycle.…”