Platelet-derived growth factor-receptor alpha strongly inhibits melanoma growth in Vitro and in Vivo.

Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. The expression of platelet-derived growth factor receptors (PDGF-Rs) is reported to be reduced in metastatic melanoma compared with benign nevi or normal skin; we then hypothesized that PDGF-R± may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-R± respond to serum with a significantly lower proliferation compared with that of controls. Apoptosis, cell cycle arrest, pRb dephosphorylation, and DNA synthesis inhibition were also observed in cells overexpressing PDGF-R±. Proliferation was rescued by PDGF-R± inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-R± mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-R± was found to mediate staurosporine cytotoxicity. A protein array–based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-R± show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/B± and a marked increase of p38³, mitogen-activated protein kinase kinase 3, and signal regulatory protein ±1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-R± reached a significant 70% inhibition of primary melanoma growth (P < .001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-R± strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.