TY - JOUR
T1 - ADP-Ribosylation factor 6 regulates tumorigenic and invasive properties in vivo
AU - Muralidharan-Chari, Vandhana
AU - Hoover, Holly
AU - Clancy, James
AU - Schweitzer, Jill
AU - Suckow, Mark A.
AU - Schroeder, Valerie
AU - Castellino, Francis J.
AU - Schorey, Jeffrey S.
AU - D'Souza-Schorey, Crislyn
PY - 2009/3/15
Y1 - 2009/3/15
N2 - This study shows that the small GTP-binding protein ADP- ribosylation factor 6 (AKF6) 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 Racl 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.
AB - This study shows that the small GTP-binding protein ADP- ribosylation factor 6 (AKF6) 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 Racl 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.
UR - http://www.scopus.com/inward/record.url?scp=65549106079&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=65549106079&partnerID=8YFLogxK
U2 - 10.1158/0008-5472.CAN-08-1301
DO - 10.1158/0008-5472.CAN-08-1301
M3 - Article
C2 - 19276388
AN - SCOPUS:65549106079
VL - 69
SP - 2201
EP - 2209
IS - 6
ER -