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      Promising Pharmacological Directions in the World of Lysophosphatidic Acid Signaling

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          Abstract

          Lysophosphatidic acid (LPA) is a signaling lipid that binds to six known lysophosphatidic acid receptors (LPARs), named LPA 1-LPA 6. These receptors initiate signaling cascades relevant to development, maintenance, and healing processes throughout the body. The diversity and specificity of LPA signaling, especially in relation to cancer and autoimmune disorders, makes LPA receptor modulation an attractive target for drug development. Several LPAR-specific analogues and small molecules have been synthesized and are efficacious in attenuating pathology in disease models. To date, at least three compounds have passed phase I and phase II clinical trials for idiopathic pulmonary fibrosis and systemic sclerosis. This review focuses on the promising therapeutic directions emerging in LPA signaling toward ameliorating several diseases, including cancer, fibrosis, arthritis, hydrocephalus, and traumatic injury.

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          The immune modulator FTY720 targets sphingosine 1-phosphate receptors.

          Volker Brinkmann, Michael D Davis, Christopher E. Heise … (2002)
          Immunosuppressant drugs such as cyclosporin have allowed widespread organ transplantation, but their utility remains limited by toxicities, and they are ineffective in chronic management of autoimmune diseases such as multiple sclerosis. In contrast, the immune modulating drug FTY720 is efficacious in a variety of transplant and autoimmune models without inducing a generalized immunosuppressed state and is effective in human kidney transplantation. FTY720 elicits a lymphopenia resulting from a reversible redistribution of lymphocytes from circulation to secondary lymphoid tissues by unknown mechanisms. Using FTY720 and several analogs, we show now that FTY720 is phosphorylated by sphingosine kinase; the phosphorylated compound is a potent agonist at four sphingosine 1-phosphate receptors and represents the therapeutic principle in a rodent model of multiple sclerosis. Our results suggest that FTY720, after phosphorylation, acts through sphingosine 1-phosphate signaling pathways to modulate chemotactic responses and lymphocyte trafficking.
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            Autotaxin has lysophospholipase D activity leading to tumor cell growth and motility by lysophosphatidic acid production

            Makiko Umezu-Goto, Yasuhiro Kishi, Akitsu Taira … (2002)
            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.

              Akira Tokumura, Eiji Majima, Yuko Kariya … (2002)
              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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                Author and article information

                Journal
                Journal ID (nlm-ta): Biomol Ther (Seoul)
                Journal ID (iso-abbrev): Biomol Ther (Seoul)
                Journal ID (publisher-id): Biomol Ther (Seoul)
                Journal ID (publisher-id): ksp
                Title: Biomolecules & Therapeutics
                Publisher: The Korean Society of Applied Pharmacology
                ISSN (Print): 1976-9148
                ISSN (Electronic): 2005-4483
                Publication date (Print): January 2015
                Publication date (Electronic): 1 January 2015
                Volume: 23
                Issue: 1
                Pages: 1-11
                Affiliations
                [1 ]Department of Molecular and Cellular Neuroscience, Dorris Neuroscience Center, The Scripps Research Institute, La Jolla, CA 92037
                [2 ]Biomedical Sciences Graduate Program, University of California, San Diego, School of Medicine, La Jolla, CA 92037, USA
                Author notes
                [* ]Corresponding Author: E-mail: jchun@ 123456scripps.edu , Tel: +1-858-784-8410, Fax: +1-858-784-7084
                Article
                Publisher ID: bt-23-1
                DOI: 10.4062/biomolther.2014.109
                PMC ID: 4286743
                PubMed ID: 25593637
                SO-VID: 0b792f24-b857-42fb-8d0b-2a347d33e0f2
                Copyright © Copyright © 2015 The Korean Society of Applied Pharmacology
                License:

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Date received : 29 September 2014
                Date revision received : 02 December 2014
                Date accepted : 02 December 2014
                Categories
                Subject: Invited Review

                Keywords: lysophosphatidic acid receptor,pharmacology,autotaxin,cancer,autoimmune disease,fibrosis
                Data availability:
                Keywords: lysophosphatidic acid receptor, pharmacology, autotaxin, cancer, autoimmune disease, fibrosis

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