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

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.

Locally expressed LHRH receptors mediate the oncostatic and antimetastatic activity of LHRH agonists on melanoma cells.

Malignant melanoma is a tumor known for its uncontrollable growth and aggressive metastatic behavior. The mean survival time for patients with a metastatic melanoma is estimated to be less than 6 months, tumor cells being refractory to the conventional chemotherapy. A better understanding of the mechanisms regulating melanoma growth and progression might help increase the number of therapeutic options for this pathology. In this paper, we have shown that LHRH receptors are present in the BLM melanoma cell line, both at mRNA and at protein level; a potent LHRH agonist (LHRH-A; Zoladex) binds to these receptors with high affinity. BLM cells also express the mRNA for LHRH, indicating the presence of an autocrine LHRH-based system in melanoma cells. The treatment of BLM cells with LHRH-A dose-dependently inhibited cell proliferation; this effect was found to be specific because it was completely abrogated by the simultaneous treatment of the cells with a LHRH antagonist. Similar observations could be obtained in another melanoma cell line (Me15392). The activation of LHRH receptors, by means of LHRH-A, also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate through a Boyden's chamber in response to a chemotactic stimulus. These data represent the first report that 1) LHRH and LHRH receptors are expressed in melanoma tumor cells; and 2) the activation of tumor LHRH receptors reduces both the proliferation and the metastatic potential of melanoma cells. It is suggested that the expression of LHRH receptors might represent a new diagnostic marker for the detection and progression of melanoma. These receptors might also be considered as a possible molecular target for a hormone-based therapeutic approach to this tumor.