Luteinizing hormone-releasing hormone (LHRH) is the key hormone in the control of reproductive functions. In recent years, it has become evident that LHRH might act as a growth modulatory factor in tumors of the reproductive system. We have shown that in prostate cancer cells LHRH is expressed, together with its receptors, to negatively regulate cell proliferation. In these cells, LHRH acts as an antimitogenic factor through the activation of the Gi-cAMP intracellular signaling pathway. More recently, we investigated whether an LHRH-based autocrine system might also be expressed in tumors that are not classically related to the reproductive tract, such as melanoma. Malignant melanoma is known to be characterized not only by a high proliferation rate, but also by an aggressive metastatic behavior. We have demonstrated that both LHRH and LHRH receptors are expressed in human melanoma cells (BLM and Me15392). Activation of LHRH receptors by means of a potent LHRH agonist (Zoladex) significantly inhibited cell proliferation. The LHRH agonist also reduced the ability of melanoma cells to invade a reconstituted basement membrane (Matrigel) and to migrate in response to a chemotactic stimulus. These data indicate that: (a) in prostate cancer cells the LHRH receptor is coupled to a Gi-cAMP signal transduction pathway; (b) LHRH and LHRH receptors are also expressed in tumors that are not classically related to the reproductive system, such as melanoma; in melanoma cells, LHRH might act as an inhibitory factor on both cell proliferation and metastatic behavior. It is suggested that, in melanoma, LHRH receptors might represent a diagnostic marker and a possible molecular target for new therapeutic approaches for this pathology.

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 M ALIGNANT MELANOMA IS a tumor known for its uncontrollable growth (1). The incidence of melanoma, which predominantly occurs in the skin, is increasing dramatically (2). The prognosis of this tumor has improved in the last decades particularly due to early diagnosis, but it remains very poor in advanced cases, when tumor cells acquire a strong potential to disseminate metastases (1). Moreover, advanced melanoma is characterized by an intrinsic resistance to chemotherapy (3-5). A recently introduced new chemotherapeutic drug for metastasized melanoma, temozolomide, failed to offer a significant improvement of mean survival compared with the treatment with the traditional cytotoxic drug DTIC (dacarbazine, Bedford Laboratories, Bedford, OH) (5). Both of these chemotherapeutics induce thrombocytopenia as a classical side effect with considerable risks because metastasis bleeding may occur, especially in cerebral metastases. Due to the ability of melanoma cells to rapidly metastasize, prevention of metastasis formation has been indicated as the main goal in melanoma treatment (6).Hypothalamic LHRH is the master hormone in reproduction; it controls pituitary-gonadal functions by activating LHRH receptors present on gonadotropin-producing cells of the adenohypophysis (7). LHRH agonists, when given continuously, suppress gonadotropin synthesis and secretion through the down-regulation of these pituitary LHRH receptors (8). This mechanism of action has provided the rationale for the wide and successful use of LHRH agonists in the treatment of hormone-dependent tumors (e.g. prostate and breast carcinoma; Refs. 9 -11). In addition, it has been shown that these tumors express both LHRH and LHRH receptors. Through the activation of these receptors, locally produced LHRH seems to behave as an autocrine-negative regulator of cancer growth. Moreover, activation of tumor LHRH receptors by exogenous LHRH agonists inhibits the proliferation of tumor cells, both in vitro and in vivo, indicating an additional and more direct antitumoral activity for these compounds (12).In a recent paper, van Groeninghen et al. (13...

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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.

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