New cGMP analogues restrain proliferation and migration of melanoma cells
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Eleonora Vighi1, Andreas Rentsch2, Philipp Henning3, Antonella Comitato1, Dorit Hoffmann1, Daniela Bertinetti3, Evelina Bertolotti1, Frank Schwede2, Friedrich W. Herberg3, Hans-Gottfried Genieser2 and Valeria Marigo1
1University of Modena and Reggio Emilia, Department of Life Sciences, 41125 Modena, Italy
2BIOLOG Life Science Institute Forschungslabor und Biochemica-Vertrieb GmbH, 28199 Bremen, Germany
3Department of Biochemistry, University of Kassel, 34132 Kassel, Germany
Valeria Marigo, email: [email protected]
Keywords: PKG2; MNT1; SkMel28; cGMP; pVASP
Received: May 04, 2017 Accepted: December 18, 2017 Published: December 25, 2017
Melanoma is one of the most aggressive cancers and displays high resistance to conventional chemotherapy underlining the need for new therapeutic strategies. The cGMP/PKG signaling pathway was detected in melanoma cells and shown to reduce migration, proliferation and to increase apoptosis in different cancer types. In this study, we evaluated the effects on cell viability, cell death, proliferation and migration of novel dimeric cGMP analogues in two melanoma cell lines (MNT1 and SkMel28). These new dimeric cGMP analogues, by activating PKG with limited effects on PKA, significantly reduced proliferation, migration and increased cell death. No decrease in cell viability was observed in non-tumor cells suggesting a tumor-specific effect. These effects observed in melanoma are possibly mediated by PKG2 activation based on the decreased toxic effects in tumor cell lines not expressing PKG2. Finally, PKG-associated phosphorylation of vasodilator-stimulated-phosphoprotein (VASP), linked to cell death, proliferation and migration was found increased and with a change of subcellular localization. Increased phosphorylation of RhoA induced by activation of PKG may also contribute to reduced migration ability of the SkMel28 melanoma cell line when treated with cGMP analogues. These findings suggest that the cGMP/PKG pathway can be envisaged as a therapeutic target of novel dimeric cGMP analogues for the treatment of melanoma.
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