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.
Cell reports. 2016 Mar 08 [Epub ahead of print]
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
Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany., Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany., Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany., Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany., Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany., Hertie-Institut für klinische Hirnforschung, Abteilung Vaskuläre Neurologie, Labor für Molekulare Neuroonkologie, 72076 Tübingen, Germany., Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland., Department of Dermatology, Inselspital, University Hospital Bern, 3010 Bern, Switzerland., Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany., Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany; Department of Dermatology and Allergology, Technische Universität München, 80802 Munich, Germany., Department of Dermatology, University of Tübingen, 72076 Tübingen, Germany., Institute of Pharmacology, University of Bern, 3010 Bern, Switzerland., Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany., Interfakultäres Institut für Biochemie, University of Tübingen, 72076 Tübingen, Germany.