Oncogenic BRAF Induces Melanoma Cell Invasion by Downregulating the cGMP-Specific Phosphodiesterase PDE5A

• Published in: Cancer cell 2011-01, Vol.19 (1), p.45-57
• Main Authors: Arozarena, Imanol, Sanchez-Laorden, Berta, Packer, Leisl, Hidalgo-Carcedo, Cristina, Hayward, Robert, Viros, Amaya, Sahai, Erik, Marais, Richard
• Format: Article
• Language: English
• Subjects: Animals; Calcimycin - pharmacology; Calcium - antagonists & inhibitors; Calcium - metabolism; Cardiac Myosins - antagonists & inhibitors; Cardiac Myosins - metabolism; Cell Line, Tumor; Cell Movement - drug effects; Cell Movement - genetics; Cell Proliferation; Cyclic GMP - analogs & derivatives; Cyclic GMP - metabolism; Cyclic GMP - pharmacology; Cyclic Nucleotide Phosphodiesterases, Type 5 - genetics; Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism; Down-Regulation - genetics; Gene Expression - drug effects; Gene Expression - genetics; Gene Expression Regulation, Neoplastic - drug effects; Gene Expression Regulation, Neoplastic - physiology; Heterocyclic Compounds, 4 or More Rings - pharmacology; Homeodomain Proteins - metabolism; Humans; Lung Neoplasms - pathology; Lung Neoplasms - prevention & control; Lung Neoplasms - secondary; Melanoma - metabolism; Melanoma - pathology; Mice; Mice, Nude; Myosin Light Chains - antagonists & inhibitors; Myosin Light Chains - metabolism; Neoplasm Invasiveness - pathology; Neoplasm Invasiveness - prevention & control; Phosphodiesterase 5 Inhibitors - pharmacology; Phosphorylation - drug effects; POU Domain Factors - metabolism; Promoter Regions, Genetic - genetics; Protein Binding - genetics; Protein Kinase Inhibitors - pharmacology; Proto-Oncogene Proteins B-raf - antagonists & inhibitors; Proto-Oncogene Proteins B-raf - genetics; Proto-Oncogene Proteins B-raf - metabolism; RNA, Small Interfering - genetics; Transplantation, Heterologous - pathology
• ISSN: 1535-6108; 1878-3686
• DOI: 10.1016/j.ccr.2010.10.029

We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca 2+, stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A. [Display omitted] ► Oncogenic BRAF downregulates PDE5A in melanoma cells ► PDE5A downregulation or inhibition induces invasion in BRAF mutant melanoma cells ► PDE5A regulates invasion by increasing cGMP, Ca 2+, and contractility in melanoma cells ► PDE5A loss increases short and long-term colonization of the lungs by melanoma cells