Novel insights into GnRH receptor activity: Role in the control of human glioblastoma cell proliferation

Abstract

Abstract. Malignant glioblastoma is one of the highest proliferative and invasive tumors within the central nervous system (CNS); the therapeutical options for this disease are still very poor. Receptors for gonadotropin-releasing hormone (GnRH) have been reported to be present in glioblastoma tissues. This study aimed to determine the role of these receptors in the control of glioma growth. In two human glioblastoma cell lines, U87MG and U373, we demonstrated the expression of GnRH receptors, both at mRNA and protein levels. We also found that GnRH receptor is expressed in glioblastoma tissues from tumor patients as shown by Western blotting. In U87MG and U373 cell lines, we found the expression of mRNA for GnRH, indicating the presence of an autocrine GnRH-based system in these cell lines. Treatment of the two cell lines with a GnRH agonist resulted in a significant decrease of cell proliferation. Moreover, the GnRH agonist significantly counteracted the forskolin-induced increase of intracellular cAMP levels in these cells. These findings suggest that the GnRH receptor might represent a molecular target for an endocrine therapeutical approach against gliomas.

Growth Hormone (GH) and Gonadotropin-Releasing Hormone (GnRH) in the Central Nervous System: A Potential Neurological Combinatory Therapy?

“…The presence of GH and GnRH receptors has been reported in tumor cell lines of neural origin and brain tumors [ 37 , 144 ]. However, it should be kept in mind that the expression of hormonal receptors is not necessarily consistent, even in the same type of tumors [ 37 , 143 , 185 ].…”

“…Autocrine and paracrine actions of GnRH through the GnRH-R in nervous system tumors have been observed in meningiomas and low-grade glioblastoma multiforme, and it has been proposed that GnRH-R could be used as a prognosis marker [ 143 , 144 ]. Interestingly, the expression of GnRH-R in many cancer cell types leads to the strategy of using it as a way to induce specific cytotoxicity through AN-152 (AEZS-108), a toxic analog of GnRH, which is internalized after binding to the receptor and subsequently accumulates until it induces cell death [ 190 ].…”

The Anti-proliferative Activity of GnRH Through Downregulation of the Akt/ERK Pathways in Pancreatic Cancer

“…Since previous studies indicated that GnRH and its receptor were expressed in various malignant tumors (10, 11, 13), we expected that GnRH expression might be associated with malignancy in pancreatic cancer. Based on the Bittner multi-cancer dataset, GnRH and GnRHR were upregulated in pancreatic cancer (Figure 1A and Supplementary Figure 1).…”

“…Harris et al showed that the gene expression of GnRH in human breast cancer cell lines (9). Moreover, the high-expression of GnRH and its receptor had been found in several cancers from non-reproductive tissues, including the urinary bladder cancer, glioblastoma, lung cancer, and breast cancer (10–12). Furthermore, a recent study indicated that GnRH agonists have strong anti-tumor activity, which can reduce cell proliferation in ovarian, endometrial, and breast cancer cells (13).…”

The Musashi1 RNA-Binding Protein: A Critical Regulator in Glioblastoma

“…GnRH-mediated signaling may be important for the growth and maintenance of gliomas. The use of the GnRH agonist Zoladex results in inhibition of cell proliferation in two glioblastoma cell lines (U87MG and U373) thus presenting GnRH signaling as a potential therapeutic target (Marelli et al, 2009).…”