NAADP-Dependent Ca(2+) Signaling Controls Melanoma Progression, Metastatic Dissemination and Neoangiogenesis

• Published in: Scientific reports 2016-01, Vol.6, p.18925-18925
• Main Authors: Favia, Annarita, Pafumi, Irene, Desideri, Marianna, Padula, Fabrizio, Montesano, Camilla, Passeri, Daniela, Nicoletti, Carmine, Orlandi, Augusto, Del Bufalo, Donatella, Sergi, Manuel, Ziparo, Elio, Palombi, Fioretta, Filippini, Antonio
• Format: Article
• Language: English
• Subjects: Animals; Calcium Signaling - drug effects; Carbolines - pharmacokinetics; Carbolines - pharmacology; Carbolines - toxicity; Cell Adhesion - drug effects; Cell Movement - drug effects; Cell Proliferation - drug effects; Cell Survival - drug effects; Disease Models, Animal; Disease Progression; Gene Expression; Male; Melanoma - drug therapy; Melanoma - genetics; Melanoma - metabolism; Melanoma - pathology; Melanoma, Experimental; Mice; NADP - analogs & derivatives; NADP - metabolism; Neoplasm Metastasis; Neovascularization, Pathologic - drug therapy; Neovascularization, Pathologic - metabolism; Piperazines - pharmacokinetics; Piperazines - pharmacology; Piperazines - toxicity; Tumor Burden - drug effects; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - pharmacology; Vascular Endothelial Growth Factor Receptor-2 - genetics; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 2045-2322
• DOI: 10.1038/srep18925

A novel transduction pathway for the powerful angiogenic factor VEGF has been recently shown in endothelial cells to operate through NAADP-controlled intracellular release of Ca(2+). In the present report the possible involvement of NAADP-controlled Ca(2+) signaling in tumor vascularization, growth and metastatic dissemination was investigated in a murine model of VEGF-secreting melanoma. Mice implanted with B16 melanoma cells were treated with NAADP inhibitor Ned-19 every second day for 4 weeks and tumor growth, vascularization and metastatization were evaluated. Control specimens developed well vascularized tumors and lung metastases, whereas in Ned-19-treated mice tumor growth and vascularization as well as lung metastases were strongly inhibited. In vitro experiments showed that Ned-19 treatment controls the growth of B16 cells in vitro, their migratory ability, adhesive properties and VEGFR2 expression, indicating NAADP involvement in intercellular autocrine signaling. To this regard, Ca(2+) imaging experiments showed that the response of B16 cells to VEGF stimulation is NAADP-dependent. The whole of these observations indicate that NAADP-controlled Ca(2+) signaling can be relevant not only for neoangiogenesis but also for direct control of tumor cells.