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

Debora Faraone, Maria Simona Aguzzi, Gabriele Toietta, Angelo M. Facchiano, Francesco Facchiano, Alessandra Magenta, Fabio Martelli, Silvia Truffa, Eleonora Cesareo, Domenico Ribatti, Maurizio C. Capogrossi, Antonio Facchiano

Research output: Contribution to journalArticle

Abstract

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-Rα may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Rα 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-Rα. Proliferation was rescued by PDGF-Rα inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Rα mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Rα was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Rα show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Bα and a marked increase of p38γ, mitogen-activated protein kinase kinase 3, and signal regulatory protein α1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Rαreached a significant 70% inhibition of primary melanoma growth (P <.001) and a similar inhibition of tumor angiogenesis. All together, these data demonstrate that PDGF-Rα strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.

Original languageEnglish
Pages (from-to)732-742
Number of pages11
JournalNeoplasia (United States)
Volume11
Issue number8
DOIs
Publication statusPublished - Aug 2009

ASJC Scopus subject areas

  • Cancer Research

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    Faraone, D., Aguzzi, M. S., Toietta, G., Facchiano, A. M., Facchiano, F., Magenta, A., Martelli, F., Truffa, S., Cesareo, E., Ribatti, D., Capogrossi, M. C., & Facchiano, A. (2009). Platelet-derived growth factor-receptor α strongly inhibits melanoma growth in Vitro and in Vivo. Neoplasia (United States), 11(8), 732-742. https://doi.org/10.1593/neo.09408