Platelet-Derived Growth Factor-Receptor α 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 alpha may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-R alpha 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 alpha. Proliferation was rescued by PDGF-R alpha inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-R alpha mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-R alpha 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 alpha show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/B alpha and a marked increase of p38 gamma, mitogen-activated protein kinase kinase 3, and signal regulatory protein alpha 1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-R alpha 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 alpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.