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ADP-Ribosylation Factor 6 Regulates Tumorigenic and Invasive Properties In vivo

¹ Department of Biological Sciences, ² Freimann Life Science Center, and ³ W.M. Keck Center for Transgene Research, University of Notre Dame, Notre Dame, Indiana

Requests for reprints: Crislyn D'Souza-Schorey, Department of Biological Sciences, University of Notre Dame, Box 369, Galvin Life Sciences Building, Notre Dame, IN 46556-0369. Phone: 574-631-3735; Fax: 574-631-7413; E-mail: D'Souza-Schorey.1{at}nd.edu or cdsouzas{at}nd.edu.

Key Words: ARF6 • tumor cell invasion • metastases • PLD • ERK

This study shows that the small GTP-binding protein ADP-ribosylation factor 6 (ARF6) is an important regulator of tumor growth and metastasis. Using spontaneous melanoma tumor growth assays and experimental metastasis assays in nude mice, we show that sustained activation of ARF6 reduces tumor mass growth but significantly enhances the invasive capacity of tumor cells. In contrast, mice injected with tumor cells expressing a dominantly inhibitory ARF6 mutant exhibited a lower incidence and degree of invasion and lung metastasis compared with control animals. Effects on tumor growth correlate with reduced cell proliferation capacity and are linked at least in part to alterations in mitotic progression induced by defective ARF6 cycling. Furthermore, phospho-ERK levels in subcultured cells from ARF6(GTP) and ARF6(GDP) tumor explants correlate with invasive capacity. ARF6-induced extracellular signal-regulated kinase (ERK) signaling leads to Rac1 activation to promote invadopodia formation and cell invasion. These findings document an intricate role for ARF6 and the regulation of ERK activation in orchestrating mechanisms underlying melanoma growth, invasion, and metastases. [Cancer Res 2009;69(6):2201–9]

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