We showed previously that
GnRH receptors are expressed in
melanoma cells; their activation reduces cell growth and metastatic behavior. Here, we investigated whether
GnRH agonists might affect the expression of genes involved in
melanoma progression. By genome-wide transcriptomic and real-time PCR analysis, we first observed that
GnRH agonists decrease the expression of the pro-
angiogenic factor vascular endothelial growth factor (
VEGF) (all
isoforms) in BLM
melanoma cells. Then, we demonstrated that
GnRH agonists specifically decrease the expression of the VEGF165
isoform as well as its secretion from BLM cells. These data suggested that activation of
GnRH receptors might reduce the pro-angiogenic behavior of
melanoma cells. To verify this hypothesis, we treated BLM cells with a
GnRH agonist; the
conditioned medium from these cells was tested to assess its capability to stimulate human umbilical vein endothelial cell (HUVEC) motility. The migration of HUVECs towards the
conditioned medium of
GnRH agonist-treated BLM cells was significantly lower than the migration of HUVECs toward the
conditioned medium of untreated cells. Thus,
GnRH agonists reduce the pro-angiogenic behavior of
melanoma cells through a decreased production of bioactive
VEGF. We then found that
GnRH receptors are also expressed on HUVECs and that
GnRH agonists reduce their ability to proliferate and to form capillary-like tubes when stimulated by
VEGF. These findings suggest that
GnRH agonists exert an anti-angiogenic activity indirectly by decreasing
VEGF secretion from
tumor cells and directly by counteracting the pro-angiogenic activity of the
growth factor. These data might lead to the development of novel targeted approaches for
melanoma.