This Article Full Text Full Text (PDF) Supplementary Data All Versions of this Article: 0008-5472.CAN-08-2110v1 69/3/794    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Hu, B. Articles by Cheng, S.-Y. Search for Related Content PubMed PubMed Citation Articles by Hu, B. Articles by Cheng, S.-Y.

ADP-Ribosylation Factor 6 Regulates Glioma Cell Invasion through the IQ-Domain GTPase-Activating Protein 1-Rac1–Mediated Pathway

¹ Cancer Institute, Departments of ² Medicine and ³ Pathology, University of Pittsburgh, Pittsburgh, Pennsylvania and ⁴ Department of Biological Sciences and The Walther Cancer Institute, University of Notre Dame, Notre Dame, Indiana

Requests for reprints: Bo Hu, University of Pittsburgh Cancer Institute and Department of Medicine, HCCLB, 2.19, 5117 Center Avenue, Pittsburgh, PA 15213. Phone: 412-623-7791; Fax: 412-623-4840; E-mail: hub{at}upmc.edu or Shi-Yuan Cheng, University of Pittsburgh Cancer Institute and Department of Pathology, HCCLB, 2.26f, 5117 Center Avenue, Pittsburgh, PA 15213. Phone: 412-623-3261; Fax: 412-623-4840; E-mail: chengs{at}upmc.edu.

Key Words: ARF6 • IQGAP1 • Rac1 • glioma • invasion

A common pathobiological feature of malignant gliomas is the insidious infiltration of single tumor cells into the brain parenchyma, rendering these deadly tumors virtually incurable with available therapies. In this study, we report that ADP-ribosylation factor 6 (ARF6), a Ras superfamily small GTPase, is abundantly expressed in invasive human glioma cells. Cellular depletion of ARF6 by small interfering RNA decreased Rac1 activation, impaired HGF-stimulated and serum-stimulated glioma cell migration in vitro, and markedly decreased the invasive capacity of invasive glioma in the brain. Furthermore, ectopic expression of ARF6 in glioma cells promoted cell migration via the activation of Rac1. Upon stimulation of glioma cells with HGF, we show that IQ-domain GTPase-activating protein 1 (IQGAP1) is recruited and overlaps with ARF6 at the leading edge of migrating cells. However, cellular depletion of ARF6 abrogated this recruitment of IQGAP1 and attenuated the formation of surface protrusions. ARF6 forms complexes with Rac1 and IQGAP1 in glioma cells upon HGF stimulation, and knockdown of IQGAP1 significantly inhibits ARF6-induced Rac1 activation and cell migration. Taken together, these data suggest that ARF6-mediated Rac1 activation is essential for glioma cell invasion via a signaling pathway that requires IQGAP1. [Cancer Res 2009;69(3):794–801]