Kishi Yasuhiro, Okudaira Shinichi, Tanaka Masayuki, Hama Kotaro, Shida Dai, Kitayama Joji, Yamori Takao, Aoki Junken, Fujimaki Takamitsu, Arai Hiroyuki
Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
J Biol Chem. 2006 Jun 23;281(25):17492-17500. doi: 10.1074/jbc.M601803200. Epub 2006 Apr 19.
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, LPA1, 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 LPA1-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 LPA1, ATX, and LPC-producing enzymes are potential targets for cancer therapy, including GBM.
自分泌运动因子（ATX）是一种多功能磷酸二酯酶，最初作为一种强大的细胞运动刺激因子从黑色素瘤细胞中分离出来。ATX与溶血磷脂酶D相同，后者可从溶血磷脂酰胆碱（LPC）产生生物活性磷脂溶血磷脂酸（LPA）。尽管已反复证明ATX在各种肿瘤组织中表达增强，因此ATX与肿瘤进展有关，但肿瘤细胞表达的ATX的确切作用尚不清楚。在本研究中，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，因其对正常脑实质的高浸润性，但在其他脑肿瘤组织中不表达。此外，负责LPA驱动细胞运动的LPA受体LPA1主要在GBM中表达。在博伊登室试验和伤口愈合试验中，显示出最高ATX表达的胶质母细胞瘤之一（SNB - 78）以及ATX稳定转染细胞对LPA表现出LPA1依赖性细胞迁移。有趣的是，这些表达ATX的细胞对LPC也表现出趋化反应。此外，在SNB - 78细胞中使用小干扰RNA技术降低ATX水平可抑制它们对LPC的迁移反应。这些结果表明，癌细胞衍生的ATX自分泌产生LPA以及外源性提供的LPC有助于癌细胞的侵袭性，并且LPA1、ATX和产生LPC的酶是包括GBM在内的癌症治疗的潜在靶点。
