Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth

• Main Authors: Sandeep Dhayade, Susanne Kaesler, Tobias Sinnberg, Hyazinth Dobrowinski, Stefanie Peters, Ulrike Naumann, He Liu, Robert E. Hunger, Martin Thunemann, Tilo Biedermann, Birgit Schittek, Hans-Uwe Simon, Susanne Feil, Robert Feil
• Format: Article
• Language: English
• Published: Elsevier 2016-03-01
• Series: Cell Reports
• Online Access: http://www.sciencedirect.com/science/article/pii/S2211124716301310

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.