GnRH Receptors in Cancer: From Cell Biology to Novel Targeted Therapeutic Strategies

• Published in: Endocrine reviews Vol. 33; no. 5; pp. 784 - 811
• Main Authors: Limonta, Patrizia, Marelli, Marina Montagnani, Mai, Stefania, Motta, Marcella, Martini, Luciano, Moretti, Roberta M
• Format: Journal Article
• Language: English
• Published: Bethesda, MD Endocrine Society 01.10.2012; Copyright by The Endocrine Society
• Subjects: Antineoplastic Agents, Hormonal - therapeutic use; Biological and medical sciences; Fundamental and applied biological sciences. Psychology; Hormone Antagonists - therapeutic use; Humans; Neoplasms - drug therapy; Neoplasms - metabolism; Receptors, LHRH - agonists; Receptors, LHRH - antagonists & inhibitors; Receptors, LHRH - metabolism; Signal Transduction - physiology; Vertebrates: endocrinology; Hypothalamic hormone; Cell biology; Gonadotropin RH; Review; Malignant tumor; Hormone releasing factor; Cancer; Biological receptor
• ISSN: 0163-769X; 1945-7189
• DOI: 10.1210/er.2012-1014

The crucial role of pituitary GnRH receptors (GnRH-R) in the control of reproductive functions is well established. These receptors are the target of GnRH agonists (through receptor desensitization) and antagonists (through receptor blockade) for the treatment of steroid-dependent pathologies, including hormone-dependent tumors. It has also become increasingly clear that GnRH-R are expressed in cancer tissues, either related (i.e. prostate, breast, endometrial, and ovarian cancers) or unrelated (i.e. melanoma, glioblastoma, lung, and pancreatic cancers) to the reproductive system. In hormone-related tumors, GnRH-R appear to be expressed even when the tumor has escaped steroid dependence (such as castration-resistant prostate cancer). These receptors are coupled to a Gαi-mediated intracellular signaling pathway. Activation of tumor GnRH-R by means of GnRH agonists elicits a strong antiproliferative, antimetastatic, and antiangiogenic (more recently demonstrated) activity. Interestingly, GnRH antagonists have also been shown to elicit a direct antitumor effect; thus, these compounds behave as antagonists of GnRH-R at the pituitary level and as agonists of the same receptors expressed in tumors. According to the ligand-induced selective-signaling theory, GnRH-R might assume various conformations, endowed with different activities for GnRH analogs and with different intracellular signaling pathways, according to the cell context. Based on these consistent experimental observations, tumor GnRH-R are now considered a very interesting candidate for novel molecular, GnRH analog-based, targeted strategies for the treatment of tumors expressing these receptors. These agents include GnRH agonists and antagonists, GnRH analog-based cytotoxic (i.e. doxorubicin) or nutraceutic (i.e. curcumin) hybrids, and GnRH-R-targeted nanoparticles delivering anticancer compounds.