Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth

• DOI: 10.1016/j.celrep.2016.02.028
• Publication Date: 2016-03-10T12:21:42Z
• 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
• Keywords: 570; QH301-705.5; 610; 610 Medicine & health; Mice; 03 medical and health sciences; Cell Movement; Cell Line, Tumor; Nitriles; Butadienes; Animals; Humans; Protein Isoforms; Biology (General); Cyclic GMP; Melanoma; Cell Proliferation; Cyclic GMP-Dependent Protein Kinase Type I; Cyclic Nucleotide Phosphodiesterases, Type 5; Mitogen-Activated Protein Kinase 1; 0303 health sciences; Mitogen-Activated Protein Kinase 3; Natriuretic Peptide, C-Type; Phosphodiesterase 5 Inhibitors; 3. Good health; Mice, Inbred C57BL; Female; Signal Transduction

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.