Cutaneous
melanoma represents the leading cause of
skin cancer deaths. The prognosis of highly aggressive, metastatic
melanoma is still very poor, due to the resistance of the disseminated
tumor to existing
therapies. The clarification of the molecular mechanisms regulating
melanoma growth and progression might help identify novel molecular targets for the development of new therapeutic interventions. We previously showed that
gonadotropin-releasing hormone (
GnRH) receptors are expressed in
melanoma cells; activation of these receptors by means of
GnRH agonists significantly reduces cell proliferation. In the current study, we first showed that
GnRH agonists significantly reduced the metastatic behavior of
melanoma cells in terms of both cell motility (haptotactic assay using
laminin as the
chemoattractant) and invasiveness (cell invasion assay evaluating the capacity of the cells to invade a reconstituted extracellular matrix barrier). On the basis of this observation, we then investigated the molecular mechanisms underlying the antimetastatic activity of
GnRH agonists. We found that, in
melanoma cells, a) the activity of the
alpha3 integrin subunit is crucial for the migratory behavior of the cells; b)
GnRH agonists significantly reduced
alpha3 integrin expression (Western blotting and immunofluorescence studies); c)
GnRH agonists significantly reduced
MMP-2 expression (comparative RT-PCR) and activity (zymographic analysis performed on cell
culture media). These data indicate that
GnRH agonists, in addition to the previously reported antiproliferative effect, elicit a strong inhibitory activity on the migratory/invasive behavior of
melanoma cells expressing
GnRH receptors. These compounds reduce the metastatic potential of
melanoma cells by interfering with the expression/activity of
cell adhesion molecules (
alpha3 integrin) and
matrix metalloproteinase (
MMP-2).