Cell reports (Cambridge), 2016-03, Vol.14 (11), p.2599-2610
2016
Details
- Autor(en) / Beteiligte
- Titel
- Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth
- Ist Teil von
- Cell reports (Cambridge), 2016-03, Vol.14 (11), p.2599-2610
- Ort / Verlag
- United States: Elsevier Inc
- Erscheinungsjahr
- 2016
- Link zum Volltext
- Quelle
- Alma/SFX Local Collection
- Beschreibungen/Notizen
- 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. [Display omitted] •Melanoma cells express a cGMP signaling pathway involving PDE5•The cGMP pathway promotes MAPK signaling and melanoma cell growth and migration•PDE5 degrades cGMP and thus acts as a brake on the growth-promoting cGMP pathway•The PDE5 blocker sildenafil releases the PDE5 brake, leading to increased tumor growth Use of the phosphodiesterase 5 inhibitor sildenafil (Viagra) has been linked to an increased risk of melanoma. Dhayade et al. explore the underlying mechanism and identify a growth-promoting cGMP-MAPK pathway in melanoma cells that is potentiated by sildenafil treatment.
- Sprache
- Englisch
- Identifikatoren
- ISSN: 2211-1247eISSN: 2211-1247DOI: 10.1016/j.celrep.2016.02.028Titel-ID: cdi_doaj_primary_oai_doaj_org_article_a642e4e467eb4035b525382257fb065e
- Format
- –
- Schlagworte
- Animals, Butadienes - pharmacology, Cell Line, Tumor, Cell Movement - drug effects, Cell Proliferation - drug effects, Cyclic GMP - metabolism, Cyclic GMP-Dependent Protein Kinase Type I - chemistry, Cyclic GMP-Dependent Protein Kinase Type I - genetics, Cyclic GMP-Dependent Protein Kinase Type I - metabolism, Cyclic Nucleotide Phosphodiesterases, Type 5 - chemistry, Cyclic Nucleotide Phosphodiesterases, Type 5 - metabolism, Female, Humans, Melanoma - drug therapy, Melanoma - metabolism, Melanoma - pathology, Mice, Mice, Inbred C57BL, Mitogen-Activated Protein Kinase 1 - antagonists & inhibitors, Mitogen-Activated Protein Kinase 1 - metabolism, Mitogen-Activated Protein Kinase 3 - antagonists & inhibitors, Mitogen-Activated Protein Kinase 3 - metabolism, Natriuretic Peptide, C-Type - toxicity, Nitriles - pharmacology, Phosphodiesterase 5 Inhibitors - pharmacology, Protein Isoforms - genetics, Protein Isoforms - metabolism, Signal Transduction - drug effects, Sildenafil Citrate - pharmacology, Sildenafil Citrate - therapeutic use, Transplantation, Homologous