ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway.
ADP-ribosylation factor 6 regulates glioma cell invasion through the IQ-domain GTPase-activating protein 1-Rac1-mediated pathway.
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DOI：
10.1158/0008-5472.can-08-2110
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发表时间：
2009-02-01
期刊：
影响因子：
11.2
通讯作者：
Cheng SY
中科院分区：
文献类型：
--
作者：
Hu B;Shi B;Jarzynka MJ;Yiin JJ;D'Souza-Schorey C;Cheng SY
恶性神经胶质瘤的一个常见病理学特征是单个肿瘤细胞隐匿性地浸润到脑实质中，使得这些致命的肿瘤几乎无法用现有的疗法治愈。在这项研究中，我们报道了 ADP-核糖基化因子 6 (ARF6)，一种 Ras 超家族小 GTP 酶，在侵袭性人胶质瘤细胞中大量表达。 siRNA对ARF6的细胞耗竭降低了Rac1的激活，损害了体外HGF和血清刺激的神经胶质瘤细胞的迁移，并显着降低了大脑中侵袭性神经胶质瘤的侵袭能力。此外，神经胶质瘤细胞中 ARF6 的异位表达通过激活 Rac1 促进细胞迁移。在用 HGF 刺激神经胶质瘤细胞后，我们发现 IQGAP1 被招募到迁移细胞前缘的 ARF6 并与之重叠。然而，细胞中 ARF6 的消耗消除了 IQGAP1 的募集并减弱了表面突起的形成。在 HGF 刺激下，ARF6 与胶质瘤细胞中的 Rac1 和 IQGAP1 形成复合物，敲低 IQGAP1 显着抑制 ARF6 诱导的 Rac1 激活和细胞迁移。总而言之，这些数据表明 ARF6 介导的 Rac1 激活对于神经胶质瘤细胞侵袭至关重要，这是通过需要 IQGAP1 的信号通路实现的。
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 siRNA decreased Rac1 activation, impaired HGF- 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 IQGAP1 is recruited to 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.