Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth

• Melanoma cells express a cGMP signaling pathway involving PDE5
• The cGMP pathway promotes MAPK signaling and melanoma cell growth and migration
• PDE5 degrades cGMP and thus acts as a brake on the growth-promoting cGMP pathway
• The PDE5 blocker sildenafil releases the PDE5 brake, leading to increased tumor growth

SummarySildenafil, 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.

Graphical AbstractFigure optionsDownload as PowerPoint slide