Dhayade, SandeepSandeepDhayadeKaesler, SusanneSusanneKaeslerSinnberg, TobiasTobiasSinnbergDobrowinski, HyazinthHyazinthDobrowinskiPeters, StefanieStefaniePetersNaumann, UlrikeUlrikeNaumannLiu, HeHeLiuHunger, RobertRobertHungerThunemann, MartinMartinThunemannBiedermann, TiloTiloBiedermannSchittek, BirgitBirgitSchittekSimon, Hans-UweHans-UweSimon0000-0002-9404-7736Feil, SusanneSusanneFeilFeil, RobertRobertFeil2024-10-242024-10-242016-03-08https://boris-portal.unibe.ch/handle/20.500.12422/140726Sildenafil, 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.en600 - Technology::610 - Medicine & healtharticle10.7892/boris.802032697199910.1016/j.celrep.2016.02.028