Inhibition of proliferation and survival of melanoma cells by adenoviral-mediated expression of dominant negative fibroblast growth factor receptor.
Melanoma is the most deadly cutaneous malignancy; its incidence has risen significantly over the last 30 years and there is no effective treatment for advanced melanoma. Autocrine expression of fibroblast growth factors (FGFs) is a common event in malignant melanoma. We therefore sought to inhibit the proliferation and survival of melanoma cells as an approach to melanoma therapy by disrupting FGF signalling via adenoviral-mediated expression of a dominant negative FGF receptor. We tested three melanoma cell lines (A375, IIB and UCD) that express FGF2 and respond to exogenous FGF2 with increased proliferation. In all three cell lines, there was a significant decrease in net proliferation, and in two (A375 and UCD) an increase in cell death, associated with expression of the dominant negative FGF receptor. In these two cell lines, expression of the dominant negative FGF receptor resulted in the accumulation of p21 (WAF1/cip1), decreased cell division cycle-2 (cdc2) kinase activity, an increase in the percentage of cells in the G2 phase of the cell cycle, and inhibition of cytokinesis, with accumulation of binucleated cells. These studies reveal that inhibition of FGF signalling can markedly decrease the net proliferation of melanoma cells by a novel mechanism involving a decrease in cdc2 kinase activity, an increase in p21 expression, inhibition of G2 progression, inhibition of cytokinesis and increased cell death. In contrast, disruption of FGF signalling had only slight effects on normal melanocytes. Disruption of FGF signalling via the expression of the dominant negative FGF receptor is, therefore, a potential therapeutic approach in human melanoma.
Ozen
Mustafa
M
Department of Pathology, Baylor College of Medicine, Texas Medical Center, Houston, Texas, USA.
Medrano
Estela E
EE
Ittmann
Michael
M
D000256:Adenoviridae / Q000235:genetics*; D016203:CDC2 Protein Kinase / Q000378:metabolism; D002455:Cell Division; D002470:Cell Survival; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000494:pharmacology; D016195:G2 Phase; D005799:Genes, Dominant / Q000502:physiology*; D015316:Genetic Therapy; D006801:Humans; D008545:Melanoma / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D017468:Receptors, Fibroblast Growth Factor / Q000502:physiology*; D012878:Skin Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000628:therapy; D014407:Tumor Cells, Cultured
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2; D016203:CDC2 Protein Kinase