Gonadotropin‐releasing hormone: GnRH receptor signaling in extrapituitary tissues

Abstract

Gonadotropin‐releasing hormone (GnRH) has historically been known as a pituitary hormone; however, in the past few years, interest has been raised in locally produced, extrapituitary GnRH. GnRH receptor (GnRHR) was found to be expressed in normal human reproductive tissues (e.g. breast, endometrium, ovary, and prostate) and tumors derived from these tissues. Numerous studies have provided evidence for a role of GnRH in cell proliferation. More recently, we and others have reported a novel role for GnRH in other aspects of tumor progression, such as metastasis and angiogenesis. The multiple actions of GnRH could be linked to the divergence of signaling pathways that are activated by GnRHR. Recent observations also demonstrate cross‐talk between GnRHR and growth factor receptors. Intriguingly, the classical Gαq–11‐phospholipase C signal transduction pathway, known to function in pituitary gonadotropes, is not involved in GnRH actions at nonpituitary targets. Herein, we review the key findings on the role of GnRH in the control of tumor growth, progression, and dissemination. The emerging role of GnRHR in actin cytoskeleton remodeling (small Rho GTPases), expression and/or activity of adhesion molecules (integrins), proteolytic enzymes (matrix metalloproteinases) and angiogenic factors is explored. The signal transduction mechanisms of GnRHR in mediating these activities is described. Finally, we discuss how a common GnRHR may mediate different, even opposite, responses to GnRH in the same tissue/cell type and whether an additional receptor(s) for GnRH exists.

Cadherin switching and activation of p120 catenin signaling are mediators of gonadotropin-releasing hormone to promote tumor cell migration and invasion in ovarian cancer

“…We and others have shown earlier that low doses of GnRH upregulate its receptor, whereas high doses decrease it (Cheung et al, 2006). This difference in regulation suggests that high levels of GnRH receptor may enhance cellular response to GnRH stimulation, presumably because of more efficient signal amplification or altered signaling through coupling to different G proteins (Cheung and Wong, 2008). In support, we found that GnRH induces cell motility and invasive response selectively in Caov-3 and OVCAR-3, which express high levels of GnRH receptor (Cheung et al, 2006;Chen et al, 2007).…”

Mutated genes, pathways and processes in tumours

“…The GnRH receptor is expressed in tumours derived from reproductive tissues, such as breast and prostate tumours, and agonists/antagonists of this receptor can be used to treat hormonedependent tumours. GnRH can also control metastasis in melanoma (Cheung & Wong, 2008). However, apart from the report that cytotoxic analogues of the GnRH receptor inhibit growth in colorectal cell lines (Szepeshazi et al, 2007), to our knowledge no previous research can account for the association between GnRH signalling and lung or colorectal tumours.…”

A case of primary aldosteronism in pregnancy: do LH and GNRH receptors have a potential role in regulating aldosterone secretion?

“…In addition to being expressed in the pituitary gland, the receptor for GNRH is found in various tissues of the reproductive system (the breast, endometrium, ovary, and prostate), in tumors derived from these tissues, and in lymphocytes. Experimental evidence has shown that this receptor and the corresponding hormone may be involved in regulating the postreceptor pathways that modulate cell proliferation, apoptosis, and angiogenesis (23). Moreover, GNRHR is able to regulate signaling pathways known to be involved in the activation of aldosterone production.…”