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      Viagra releases the brakes on melanoma growth

      Author(s):   1
      Publication date Created:
      Publication date (Electronic):
      Journal: Molecular & Cellular Oncology
      Publisher: Informa UK Limited

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          Abstract

          Use of the phosphodiesterase 5 (PDE5) blocker sildenafil (Viagra) has been linked to an increased risk of melanoma. In a recent study we discovered a growth-promoting cGMP pathway in melanoma cells. cGMP degradation via PDE5 acts as a brake on this pathway. Inhibition of PDE5 releases this brake, providing a mechanism for the promelanoma effects of sildenafil.

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          Oncogenic BRAF induces melanoma cell invasion by downregulating the cGMP-specific phosphodiesterase PDE5A.

          Cristina Hidalgo, Richard Marais, Amaya Viros … (2011)
          We show that in melanoma cells oncogenic BRAF, acting through MEK and the transcription factor BRN2, downregulates the cGMP-specific phosphodiesterase PDE5A. Although PDE5A downregulation causes a small decrease in proliferation, its major impact is to stimulate a dramatic increase in melanoma cell invasion. This is because PDE5A downregulation leads to an increase in cGMP, which induces an increase in cytosolic Ca(2+), stimulating increased contractility and inducing invasion. PDE5A downregulation also this leads to an increase in short-term and long-term colonization of the lungs by melanoma cells. We do not observe this pathway in NRAS mutant melanoma or BRAF mutant colorectal cells. Thus, we show that in melanoma cells oncogenic BRAF induces invasion through downregulation of PDE5A. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Sildenafil use and increased risk of incident melanoma in US men: a prospective cohort study.

            Wen-Qing Li, Abrar A Qureshi, Kathleen C Robinson … (2014)
            The RAS/RAF/mitogen-activated protein kinase and extracellular signal-regulated kinase (ERK) kinase/ERK cascade plays a crucial role in melanoma cell proliferation and survival. Sildenafil citrate (Viagra) is a phosphodiesterase (PDE) 5A inhibitor commonly used for erectile dysfunction. Recent studies have shown that BRAF activation down-regulates PDE5A levels, and low PDE5A expression by BRAF activation or sildenafil use increases the invasiveness of melanoma cells, which raises the possible adverse effect of sildenafil use on melanoma risk.
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              Sildenafil Potentiates a cGMP-Dependent Pathway to Promote Melanoma Growth.

              Robert Feil, Stefanie Peters, Ulrike Naumann … (2016)
              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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                Author and article information

                Journal
                Title: Molecular & Cellular Oncology
                Abbreviated Title: Molecular & Cellular Oncology
                Publisher: Informa UK Limited
                ISSN (Electronic): 2372-3556
                Publication date Created: September 18 2017
                Publication date Created: September 03 2017
                Publication date (Electronic): May 31 2016
                Publication date (Print): September 03 2017
                Volume: 4
                Issue: 5
                Page: e1188874
                Affiliations
                [1 ] Interfakultäres Institut für Biochemie, University of Tübingen, Tübingen, Germany
                Article
                DOI: 10.1080/23723556.2016.1188874
                PMC ID: 5644484
                PubMed ID: 29057299
                SO-VID: d8932f06-e853-4419-8f8b-9aa79812b383
                Copyright © © 2017
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