Abstract
Sildenafil, an inhibitor of the cGMP-degrading phosphodiesterase 5 that is used to treat erectile dysfunction, has been linked to an increased risk of melanoma. Here, we have examined the potential connection between cGMP-dependent signaling cascades and melanoma growth. Using a combination of biochemical assays and real-time monitoring of melanoma cells, we report a cGMP-dependent growth-promoting pathway in murine and human melanoma cells. We document that C-type natriuretic peptide (CNP), a ligand of the membrane-bound guanylate cyclase B, enhances the activity of cGMP-dependent protein kinase I (cGKI) in melanoma cells by increasing the intracellular levels of cGMP. Activation of this cGMP pathway promotes melanoma cell growth and migration in a p44/42 MAPK-dependent manner. Sildenafil treatment further increases intracellular cGMP concentrations, potentiating activation of this pathway. Collectively, our data identify this cGMP-cGKI pathway as the link between sildenafil usage and increased melanoma risk.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Butadienes / pharmacology
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Cell Line, Tumor
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Cell Movement / drug effects
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Cell Proliferation / drug effects
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Cyclic GMP / metabolism*
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Cyclic GMP-Dependent Protein Kinase Type I / chemistry
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Cyclic GMP-Dependent Protein Kinase Type I / genetics
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Cyclic GMP-Dependent Protein Kinase Type I / metabolism
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Cyclic Nucleotide Phosphodiesterases, Type 5 / chemistry
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Cyclic Nucleotide Phosphodiesterases, Type 5 / metabolism
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Female
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Humans
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Melanoma / drug therapy
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Melanoma / metabolism
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Melanoma / pathology
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Mice
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Mice, Inbred C57BL
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Mitogen-Activated Protein Kinase 1 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 1 / metabolism
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Mitogen-Activated Protein Kinase 3 / antagonists & inhibitors
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Mitogen-Activated Protein Kinase 3 / metabolism
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Natriuretic Peptide, C-Type / toxicity
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Nitriles / pharmacology
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Phosphodiesterase 5 Inhibitors / pharmacology
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Protein Isoforms / genetics
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Protein Isoforms / metabolism
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Signal Transduction / drug effects*
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Sildenafil Citrate / pharmacology*
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Sildenafil Citrate / therapeutic use
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Transplantation, Homologous
Substances
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Butadienes
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Nitriles
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Phosphodiesterase 5 Inhibitors
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Protein Isoforms
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U 0126
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Natriuretic Peptide, C-Type
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Sildenafil Citrate
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Cyclic GMP-Dependent Protein Kinase Type I
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Mitogen-Activated Protein Kinase 1
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Mitogen-Activated Protein Kinase 3
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Cyclic Nucleotide Phosphodiesterases, Type 5
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Cyclic GMP