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Cyclic AMP Signaling as a Mediator of Vasculogenic Mimicry in Aggressive Human Melanoma Cells In vitro

Institut National de la Sante et de la Recherche Medicale UMR911, Centre de Recherche en Oncologie Biologique et Onco-pharmacologie, Aix-Marseille University, School of Medicine Timone, Marseille, France

Requests for reprints: Patrick Verrando, Institut National de la Sante et de la Recherche Medicale UMR911, Faculté de Médecine Timone, 27 Boulevard Jean Moulin, 13385 Marseille cedex, France. Phone: 33491324409; Fax: 33491324409; E-mail: patrick.verrando{at}univmed.fr.

Key Words: cyclic AMP • Epac • vasculogenic mimicry • melanoma • signaling

Aggressive melanoma cells can engage in a process termed vasculogenic mimicry (VM) that reflects the ability of tumor cells to express a multipotent, stem cell–like phenotype. Melanoma cell plasticity contributes to the lack of efficient therapeutic strategies targeting metastatic tumors. This study reveals cyclic AMP as a mediator of VM in vitro. In uveal and cutaneous metastatic aggressive human melanoma cells, an increase in cyclic AMP by forskolin, dibutyryl cyclic AMP, or G protein–coupled receptor (GPCR) ligands such as adrenaline and vasoactive intestinal peptide inhibited VM to different extents. Although chemical modulators of protein kinase A (PKA) had no effect, a specific pharmacologic activator of Exchange protein directly activated by cyclic AMP (Epac) impaired VM. Ras-associated protein-1 (Rap1) activation assays revealed that cyclic AMP–elevating agents induce a PKA-independent activation of Epac/Rap1. Pharmacologic inhibition of extracellular signal-regulated kinase 1/2 (ERK1/2) activity abolished VM. Phosphorylation of ERK1/2 was PKA-independently inhibited by forskolin but not inhibited by Epac/Rap1 signaling, PKA modulation, or GPCR ligands. Furthermore, the forskolin also inhibited phosphatidyl inositol-3-kinase (PI3K)-mediated activation of protein kinase Akt, as monitored by Ser473 phosphorylation. The pharmacologic activation of Epac and GPCR ligands slightly stimulated Akt, a likely concomitant process of VM modulation. Collectively, these data show that forskolin strongly inhibits VM through PKA-independent activation of Epac/Rap1, PKA-, and Epac-independent inactivation of ERK1/2 and inhibition of PI3K/Akt. The data also show that VM inhibition by GPCR ligands involves mainly the Epac/Rap1-activated signal. Thus cyclic AMP inhibits VM through multiple signaling pathways. [Cancer Res 2009;69(3):802–9]

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