title: Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth.
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.
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Sandeep
authors.initials: S
authors.lastname: Dhayade
authors.affiliation: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Kaesler
authors.affiliation: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Tobias
authors.initials: T
authors.lastname: Sinnberg
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Hyazinth
authors.initials: H
authors.lastname: Dobrowinski
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Peters
authors.affiliation: Hertie-Institut für klinische Hirnforschung, Abteilung Vaskuläre Neurologie, Labor für Molekulare Neuroonkologie, 72076 Tübingen, Germany.
authors.forename: Ulrike
authors.initials: U
authors.lastname: Naumann
authors.affiliation: Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
authors.forename: He
authors.initials: H
authors.lastname: Liu
authors.affiliation: Department of Dermatology, Inselspital, University Hospital Bern, 3010 Bern, Switzerland.
authors.forename: Robert E
authors.initials: RE
authors.lastname: Hunger
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Thunemann
authors.affiliation: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany; Department of Dermatology and Allergology, Technische Universität München, 80802 Munich, Germany.
authors.forename: Tilo
authors.initials: T
authors.lastname: Biedermann
authors.affiliation: Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Birgit
authors.initials: B
authors.lastname: Schittek
authors.affiliation: Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland.
authors.forename: Hans-Uwe
authors.initials: HU
authors.lastname: Simon
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.
authors.forename: Susanne
authors.initials: S
authors.lastname: Feil
authors.affiliation: Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany. Electronic address: robert.feil@uni-tuebingen.de.
authors.forename: Robert
authors.initials: R
authors.lastname: Feil
mesh_terms: D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D006152:Cyclic GMP / Q000378:metabolism*; D062965:Cyclic GMP-Dependent Protein Kinase Type I / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5 / Q000737:chemistry / Q000378:metabolism; D005260:Female; D006801:Humans; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D020098:Natriuretic Peptide, C-Type / Q000633:toxicity; D009570:Nitriles / Q000494:pharmacology; D058986:Phosphodiesterase 5 Inhibitors / Q000494:pharmacology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects*; D000068677:Sildenafil Citrate / Q000494:pharmacology* / Q000627:therapeutic use; D014184:Transplantation, Homologous
chemical_list: D002070:Butadienes; D009570:Nitriles; D058986:Phosphodiesterase 5 Inhibitors; D020033:Protein Isoforms; C113580:U 0126; D020098:Natriuretic Peptide, C-Type; D000068677:Sildenafil Citrate; D062965:Cyclic GMP-Dependent Protein Kinase Type I; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D054706:Cyclic Nucleotide Phosphodiesterases, Type 5; D006152:Cyclic GMP