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

Abstract

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]

Bergamottin, a natural furanocoumarin abundantly present in grapefruit juice, suppresses the invasiveness of human glioma cells via inactivation of Rac1 signaling

“…Rac1 has been identified as a key regulator of cancer cell invasion (6)(7)(8). C6 glioma cells with high Rac1 activity possess increased invasiveness compared with those with low Rac1 activity (19), indicating a favorable role for Rac1 in glioma invasion.…”

“…Rac1 is one of the most studied Rho GTPase family members (5). Several lines of evidence indicate that Rac1 activation contributes to glioma cell invasion (6)(7)(8). Nakada et al (6) reported that the ephrin-B3 ligand facilitates the invasion of glioma cells through activation of Rac1.…”

Expression Profile of Genes Modulated by Aloe emodin in Human U87 Glioblastoma Cells

“…It plays crucial roles in signal transduction pathway that control proliferation, adhesion, and migration of cells during embryonic development, invasiveness of tumour cells (Jin et al, 2007) as well as apoptosis (Sun et al, 2006). The expression of RAC1 is important for cell growth, motility and morphology in glioma cells (Hu et al, 2009;Moniz et al, 2013). Blockade of RAC1 signalling in tissue remodelling promotes the accumulation of type I collagen due to decreased collagenase activity (Igata et al, 2010).…”

Arf6 coordinates actin assembly through the WAVE complex, a mechanism usurped by Salmonella to invade host cells

“…Arf6 also has a clear role in cortical cytoskeleton rearrangement (5). This is strongly supported by evidence of Arf6 and Rac1 (Ras-related C3 botulinum toxin substrate) interplay (6), exemplified by Arf6 recruitment of the Rac1 GEF Kalirin, Arf6 promotion of Rac1 activation, and lamellipodia formation (7)(8)(9).…”