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-Ralpha may control growth of melanoma cells. We show here that melanoma cells overexpressing PDGF-Ralpha 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-Ralpha. Proliferation was rescued by PDGF-Ralpha inhibitors, allowing to exclude nonspecific toxic effects and indicating that PDGF-Ralpha mediates autocrine antiproliferation signals in melanoma cells. Accordingly, PDGF-Ralpha was found to mediate staurosporine cytotoxicity. A protein array-based analysis of the mitogen-activated protein kinase pathway revealed that melanoma cells overexpressing PDGF-Ralpha show a strong reduction of c-Jun phosphorylated in serine 63 and of protein phosphatase 2A/Balpha and a marked increase of p38gamma, mitogen-activated protein kinase kinase 3, and signal regulatory protein alpha1 protein expression. In a mouse model of primary melanoma growth, infection with the Ad-vector overexpressing PDGF-Ralpha 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-Ralpha strongly impairs melanoma growth likely through autocrine mechanisms and indicate a novel endogenous mechanism involved in melanoma control.
Faraone
Debora
D
Laboratorio Biologia Vascolare e Terapia Genica, Centro Cardiologico Monzino, IRCCS, Milano, Italy.
Aguzzi
Maria Simona
MS
Toietta
Gabriele
G
Facchiano
Angelo M
AM
Facchiano
Francesco
F
Magenta
Alessandra
A
Martelli
Fabio
F
Truffa
Silvia
S
Cesareo
Eleonora
E
Ribatti
Domenico
D
Capogrossi
Maurizio C
MC
Facchiano
Antonio
A
D000818:Animals; D000943:Antigens, Differentiation / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D020287:In Situ Nick-End Labeling; D048371:MAP Kinase Kinase 3 / Q000235:genetics / Q000378:metabolism; D008545:Melanoma / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D048291:Mitogen-Activated Protein Kinase 12 / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation; D040081:Protein Array Analysis; D054648:Protein Phosphatase 2 / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000235:genetics / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism*; D011971:Receptors, Immunologic / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics / Q000378:metabolism*; D014162:Transfection
D000943:Antigens, Differentiation; D016755:Proto-Oncogene Proteins c-jun; D011971:Receptors, Immunologic; C501920:SIRPA protein, human; D048291:Mitogen-Activated Protein Kinase 12; D020796:Receptor, Platelet-Derived Growth Factor alpha; D048371:MAP Kinase Kinase 3; D054648:Protein Phosphatase 2