title: Autotaxin is overexpressed in glioblastoma multiforme and contributes to cell motility of glioblastoma by converting lysophosphatidylcholine to lysophosphatidic acid.
abstract: 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.
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Kishi
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Shinichi
authors.initials: S
authors.lastname: Okudaira
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Masayuki
authors.initials: M
authors.lastname: Tanaka
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Kotaro
authors.initials: K
authors.lastname: Hama
authors.affiliation: Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Dai
authors.initials: D
authors.lastname: Shida
authors.affiliation: Graduate School of Medicine, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Joji
authors.initials: J
authors.lastname: Kitayama
authors.affiliation: Division of Molecular Pharmacology, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Toshima-ku, Tokyo 170-8455.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033. Electronic address: jaoki@mol.f.u-tokyo.ac.jp.
authors.forename: Junken
authors.initials: J
authors.lastname: Aoki
authors.affiliation: Department of Neurosurgery, Teikyo University School of Medicine, 2-11-1, Kaga, Itabashi-ku, Tokyo 173-8605, Japan.
authors.forename: Takamitsu
authors.initials: T
authors.lastname: Fujimaki
authors.affiliation: Graduate School of Pharmaceutical Sciences, the University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Arai
mesh_terms: D015153:Blotting, Western; D001921:Brain / Q000378:metabolism; D045744:Cell Line, Tumor; D002465:Cell Movement; D004591:Electrophoresis, Polyacrylamide Gel; D015972:Gene Expression Regulation, Neoplastic; D005909:Glioblastoma / Q000378:metabolism*; D006801:Humans; D008244:Lysophosphatidylcholines / Q000378:metabolism*; D008246:Lysophospholipids / Q000378:metabolism*; D008954:Models, Biological; D009097:Multienzyme Complexes / Q000096:biosynthesis* / Q000502:physiology*; D043264:Phosphodiesterase I / Q000096:biosynthesis* / Q000502:physiology*; D010727:Phosphoric Diester Hydrolases / Q000737:chemistry; D011755:Pyrophosphatases / Q000096:biosynthesis* / Q000502:physiology*; D013997:Time Factors; D014162:Transfection; D000099189:Lysophospholipase D
chemical_list: D008244:Lysophosphatidylcholines; D008246:Lysophospholipids; D009097:Multienzyme Complexes; D043264:Phosphodiesterase I; D010727:Phosphoric Diester Hydrolases; D011755:Pyrophosphatases; D000099189:Lysophospholipase D; C032881:lysophosphatidic acid