Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth.

Dhayade, Sandeep; Kaesler, Susanne; Sinnberg, Tobias; Dobrowinski, Hyazinth; Peters, Stefanie; Naumann, Ulrike; Liu, He; Hunger, Robert E.; Thunemann, Martin; Biedermann, Tilo; Schittek, Birgit; Simon, Hans-Uwe; Feil, Susanne; Feil, Robert (2016). Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth. Cell reports, 14(11), pp. 2599-2610. Cell Press 10.1016/j.celrep.2016.02.028

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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.

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