Role of lysophosphatidic acid and rho in glioma cell motility.
Role of lysophosphatidic acid and rho in glioma cell motility.
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DOI：
10.1002/(sici)1097-0169(200003)45:3
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发表时间：
2000-03
影响因子：
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通讯作者：
T. Manning;Julie C. Parker;Harald Sontheimer
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文献类型：
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作者：
T. Manning;Julie C. Parker;Harald Sontheimer
我们研究了生物活性磷脂溶血磷脂酸 (LPA) 对源自高度侵袭性人多形性胶质母细胞瘤 (GBM) 的细胞系的影响。使用 Transwell 迁移测定，我们表明 LPA 刺激神经胶质瘤细胞的趋化迁移和趋化迁移。血脑屏障破坏和血清成分（最有可能包括 LPA）渗漏是 GBM 的常见特征。因此，LPA 对神经胶质瘤细胞运动的影响很有趣，因为在体内，GBM 细胞经常从主肿瘤迁移很远的距离，使得成功的治疗极其困难。我们在此表明 LPA 在神经胶质瘤细胞中启动多种信号级联反应。 LPA 增强的跨孔迁移对百日咳毒素 (PTX) 处理敏感，表明 G 蛋白的 G(i) 亚型具有重要作用。 LPA 还刺激 Ca(2+) 波动和细胞外信号调节激酶 (ERKS) 1 和 2 的激活，尽管阻断任一途径对神经胶质瘤细胞迁移影响不大。神经胶质瘤细胞暴露于 LPA 会导致肌球蛋白 II 的调节轻链 (RLC) 磷酸化，并形成应力纤维和粘着斑。这些效应可被 Rho 激活 ROCK 激酶抑制剂 Y-27632 阻断。延时视频显微镜显示，Y-27632 处理导致细胞呈现细长形态，表明收缩装置存在缺陷。此外，当 Rho/ROCK 激酶级联受到抑制时，许多细胞表现出明显的过程延长。上述结果表明LPA/Rho信号级联在神经胶质瘤细胞运动中发挥重要作用，肿瘤细胞在体内暴露于LPA可能有助于其侵袭表型。
We have studied the effects of the bioactive phospholipid lysophosphatidic acid (LPA) on cell lines derived from highly invasive human glioblastoma multiforme (GBM). Using transwell migration assays, we show that LPA stimulates both chemokinetic and chemotactic migration of glioma cells. Blood brain barrier breakdown and leakage of serum components that most likely include LPA are common features of GBM. Therefore, the effects of LPA on glioma cell motility are intriguing given the fact that, in vivo, GBM cells often migrate great distances from the main tumor, rendering successful therapy extremely difficult. We show here that LPA initiates a variety of signaling cascades in glioma cells. LPA-enhanced transwell migration was sensitive to pertussis toxin (PTX) treatment suggesting an important role for G(i) subtype of G proteins. LPA also stimulated Ca(2+) fluctuations and activation of extracellular signal-regulated kinases (ERKS) 1 and 2, although blocking either pathway had little effect on glioma cell migration. Exposure of glioma cells to LPA resulted in phosphorylation of the regulatory light chain (RLC) of myosin II and the formation of stress fibers and focal adhesions. These effects were blocked by Y-27632, an inhibitor of Rho-activated ROCK kinases. Time-lapse video microscopy revealed that Y-27632-treatment caused cells to assume long thin morphologies that suggested deficiencies in the contractile apparatus. Furthermore, many cells exhibited a conspicuous extension of processes when Rho/ROCK kinase cascades were inhibited. The above results suggest that LPA/Rho signaling cascades play important roles in glioma cell motility and that exposure of tumor cells to LPA in vivo may contribute to their invasive phenotype.