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      A Novel Highly Potent Autotaxin/ENPP2 Inhibitor Produces Prolonged Decreases in Plasma Lysophosphatidic Acid Formation In Vivo and Regulates Urethral Tension

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          Abstract

          Autotaxin, also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2), is a secreted enzyme that has lysophospholipase D activity, which converts lysophosphatidylcholine to bioactive lysophosphatidic acid. Lysophosphatidic acid activates at least six G-protein coupled recpetors, which promote cell proliferation, survival, migration and muscle contraction. These physiological effects become dysfunctional in the pathology of cancer, fibrosis, and pain. To date, several autotaxin/ENPP2 inhibitors have been reported; however, none were able to completely and continuously inhibit autotaxin/ENPP2 in vivo. In this study, we report the discovery of a highly potent autotaxin/ENPP2 inhibitor, ONO-8430506, which decreased plasma lysophosphatidic acid formation.

          The IC 50 values of ONO-8540506 for lysophospholipase D activity were 6.4–19 nM for recombinant autotaxin/ENPP2 proteins and 4.7–11.6 nM for plasma from various animal species. Plasma lysophosphatidic acid formation during 1-h incubation was almost completely inhibited by the addition of >300 nM of the compound to human plasma. In addition, when administered orally to rats at a dose of 30 mg/kg, the compound demonstrated good pharmacokinetics in rats and persistently inhibited plasma lysophosphatidic acid formation even at 24 h after administration.

          Smooth muscle contraction is a known to be promoted by lysophosphatidic acid. In this study, we showed that dosing rats with ONO-8430506 decreased intraurethral pressure accompanied by urethral relaxation. These findings demonstrate the potential of this autotaxin/ENPP2 inhibitor for the treatment of various diseases caused by lysophosphatidic acid, including urethral obstructive disease such as benign prostatic hyperplasia.

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          Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

          Autotaxin (ATX) is a tumor cell motility–stimulating factor, originally isolated from melanoma cell supernatants. ATX had been proposed to mediate its effects through 5′-nucleotide pyrophosphatase and phosphodiesterase activities. However, the ATX substrate mediating the increase in cellular motility remains to be identified. Here, we demonstrated that lysophospholipase D (lysoPLD) purified from fetal bovine serum, which catalyzes the production of the bioactive phospholipid mediator, lysophosphatidic acid (LPA), from lysophosphatidylcholine (LPC), is identical to ATX. The Km value of ATX for LPC was 25-fold lower than that for the synthetic nucleoside substrate, p-nitrophenyl-tri-monophosphate. LPA mediates multiple biological functions including cytoskeletal reorganization, chemotaxis, and cell growth through activation of specific G protein–coupled receptors. Recombinant ATX, particularly in the presence of LPC, dramatically increased chemotaxis and proliferation of multiple different cell lines. Moreover, we demonstrate that several cancer cell lines release significant amounts of LPC, a substrate for ATX, into the culture medium. The demonstration that ATX and lysoPLD are identical suggests that autocrine or paracrine production of LPA contributes to tumor cell motility, survival, and proliferation. It also provides potential novel targets for therapy of pathophysiological states including cancer.
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            Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.

            We purified human plasma lysophospholipase D that produces physiologically active lysophosphatidic acid and showed that it is a soluble form of autotaxin, an ecto-nucleotide pyrophosphatase/phosphodiesterase, originally found as a tumor cell motility-stimulating factor. Its lower K(m) value for a lysophosphatidylcholine than that for a synthetic substrate of nucleotide suggests that lysophosphatidylcholine is a more likely physiological substrate for autotaxin and that its predicted physiological and pathophysiological functions could be mediated by its activity to produce lysophosphate acid, an intercellular mediator. Recombinant autotaxin was found to have lysophospholipase D activity; its substrate specificity and metal ion requirement were the same as those of the purified plasma enzyme. The activity of lysophospholipase D for exogenous lysophosphatidylcholine in human serum was found to increase in normal pregnant women at the third trimester of pregnancy and to a higher extent in patients in threatened preterm delivery, suggesting its roles in induction of parturition.
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              Autotaxin stabilizes blood vessels and is required for embryonic vasculature by producing lysophosphatidic acid.

              Autotaxin (ATX) is a cancer-associated motogen that has multiple biological activities in vitro through the production of bioactive small lipids, lysophosphatidic acid (LPA). ATX and LPA are abundantly present in circulating blood. However, their roles in circulation remain to be solved. To uncover the physiological role of ATX we analyzed ATX knock-out mice. In ATX-null embryos, early blood vessels appeared to form properly, but they failed to develop into mature vessels. As a result ATX-null mice are lethal around embryonic day 10.5. The phenotype is much more severe than those of LPA receptor knock-out mice reported so far. In cultured allantois explants, neither ATX nor LPA was angiogenic. However, both of them helped to maintain preformed vessels by preventing disassembly of the vessels that was not antagonized by Ki16425, an LPA receptor antagonist. In serum from heterozygous mice both lysophospholipase D activity and LPA level were about half of those from wild-type mice, showing that ATX is responsible for the bulk of LPA production in serum. The present study revealed a previously unassigned role of ATX in stabilizing vessels through novel LPA signaling pathways.
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                Author and article information

                Contributors
                Role: Editor
                Journal
                PLoS One
                PLoS ONE
                plos
                plosone
                PLoS ONE
                Public Library of Science (San Francisco, USA )
                1932-6203
                2014
                18 April 2014
                : 9
                : 4
                : e93230
                Affiliations
                [1 ]Exploratory Research Laboratories, ONO Pharmaceutical Co., Ltd., Tsukuba, Ibaraki, Japan
                [2 ]Medicinal Chemistry Research Laboratories, ONO Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka, Japan
                [3 ]Discovery Technology Laboratories, ONO Pharmaceutical Co., Ltd., Shimamoto, Mishima, Osaka, Japan
                [4 ]Safety Research Laboratories, ONO Phamaceutical Co., Ltd., Sakai, Fukui, Japan
                The University of Tennessee Health Science Center, United States of America
                Author notes

                Competing Interests: All authors are employees of Ono Pharmaceutical Co. Ltd. This does not alter the authors' adherence to PLOS ONE policies on sharing data and materials.

                Conceived and designed the experiments: HS TS SN KK. Performed the experiments: HS AO AH MK TM HM YT YK HO NM MS. Analyzed the data: HS AH MK TM YT YK NM MS. Contributed reagents/materials/analysis tools: HS AO MK TM TS. Wrote the paper: HS AH MK TM KK.

                Article
                PONE-D-13-51018
                10.1371/journal.pone.0093230
                3991570
                24747415
                6d7ac65d-bf61-453e-a247-8a7ab3324b9f
                Copyright @ 2014

                This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

                History
                : 3 December 2013
                : 2 March 2014
                Page count
                Pages: 9
                Funding
                This study was funded by Ono Pharmaceutical Co. Ltd. The funders had role in study design, data collection and analysis, decision to publish and preparation of the manuscript.
                Categories
                Research Article
                Biology and Life Sciences
                Biochemistry
                Lipids
                Lipid Mediators
                Proteins
                Plasma Proteins
                Organisms
                Animals
                Vertebrates
                Mammals
                Rodents
                Rats
                Medicine and Health Sciences
                Clinical Medicine
                Pharmacology
                Drug Research and Development
                Pharmacodynamics
                Pharmacokinetics
                Urology
                Prostate Diseases
                Benign Prostatic Hyperplasia
                Research and Analysis Methods
                Model Organisms
                Animal Models

                Uncategorized
                Uncategorized

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