Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine TO lysophosphatidic acid
Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine TO lysophosphatidic acid
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DOI：
10.1074/jbc.m601803200
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发表时间：
2006-06-23
影响因子：
4.8
通讯作者：
Arai, Hiroyuki
中科院分区：
文献类型：
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作者：
Kishi, Yasuhiro;Okudaira, Shinichi;Arai, Hiroyuki
自分泌运动因子（ATX）是一种多功能的磷酸二酯酶，最初从黑色素瘤细胞中分离出来，作为一种有效的细胞运动刺激因子。ATX与溶血磷脂酶D相同，后者从溶血磷脂酰胆碱（LPC）产生生物活性磷脂溶血磷脂酸（LPA）。尽管已经反复证明ATX在各种肿瘤组织中的增强表达，并且因此ATX涉及肿瘤的进展，但是由肿瘤细胞表达的ATX的精确作用尚不清楚。在这项研究中，我们发现ATX在多形性胶质母细胞瘤（GBM）中高度表达，GBM是最恶性的胶质瘤，由于其高度浸润到正常脑实质中，但在其他脑肿瘤的组织中不表达。此外，LPA（1），一种负责LPA驱动的细胞运动的LPA受体，主要在GBM中表达。在Boyden小室和伤口愈合试验中，一个显示最高ATX表达的胶质母细胞瘤（SNB-78）以及ATX稳定的转染子均显示LPA（1）依赖性细胞迁移。有趣的是，这些ATX表达细胞也显示出对LPC的趋化反应。此外，在SNB-78细胞中使用小干扰RNA技术敲低ATX水平抑制了它们对LPC的迁移反应。这些结果表明，由癌细胞衍生的ATX和外源性提供的LPC自分泌产生的LPA有助于癌细胞的侵袭性，并且LPA（1）、ATX和LPC产生酶是癌症治疗（包括GBM）的潜在靶点。
Autotaxin (ATX) is a multifunctional phosphodiesterase originally isolated from melanoma cells as a potent cell motility-stimulating factor. ATX is identical to lysophospholipase D, which produces a bioactive phospholipid, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC). Although enhanced expression of ATX in various tumor tissues has been repeatedly demonstrated, and thus, ATX is implicated in progression of tumor, the precise role of ATX expressed by tumor cells was unclear. In this study, we found that ATX is highly expressed in glioblastoma multiforme (GBM), the most malignant glioma due to its high infiltration into the normal brain parenchyma, but not in tissues from other brain tumors. In addition, LPA(1), an LPA receptor responsible for LPA-driven cell motility, is predominantly expressed in GBM. One of the glioblastomas that showed the highest ATX expression (SNB-78), as well as ATX-stable transfectants, showed LPA(1)-dependent cell migration in response to LPA in both Boyden chamber and wound healing assays. Interestingly these ATX-expressing cells also showed chemotactic response to LPC. In addition, knockdown of the ATX level using small interfering RNA technique in SNB-78 cells suppressed their migratory response to LPC. These results suggest that the autocrine production of LPA by cancer cell-derived ATX and exogenously supplied LPC contribute to the invasiveness of cancer cells and that LPA(1), ATX, and LPC-producing enzymes are potential targets for cancer therapy, including GBM.