Platelet derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo
Faraone D, Aguzzi MS, Toletta G, Facchiano AM, Facchiano F, Magenta A, Martelli F, Truffa S, Cesareo E, Ribatti D, Capogrossi MC and Facchiano A. Platelet derived growth factor-receptor alpha strongly inhibits melanoma growth in vitro and in vivo. Neoplasia, 2009 Aug;11(8):732-742
Cutaneous melanoma is the most aggressive skin cancer; it is highly metastatic and responds poorly to current therapies. Platelet Derived Growth Factor Receptors (PDGF-Rs) expression is reported to be reduced in metastatic melanoma, compared to benign nevi or normal skin; we then hypothesized that PDGF-Ralpha may control melanoma cells growth. We show here that melanoma cells over-expressing PDGF-Ralpha respond to serum with a significantly lower proliferation as compared to controls. Apoptosis, cell cycle arrest, pRb de-phosphorylation and DNA synthesis-inhibition were also observed in cells over-expressing PDGF-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude non-specific toxic effects and indicating that PDGF-Ralpha mediates autocrine anti-proliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the MAP-kinase pathway revealed that melanoma cells over-expressing PDGF-Ralpha show strong reduction of c-Jun phosphorylated in serine 63 and of PP2A/Balpha phosphatase, and marked increase of p38 gamma, MKK3 and SIRPalpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector over-expressing PDGF-Ralpha reached a significant 70% inhibition of primary melanoma growth (p<0.001) and a similar inhibition of tumor-angiogenesis. All together these data demonstrate that PDGF-Ralpha strongly impairs melanoma growth likely via autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.