Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

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Abstract

Lysophosphatidic acid (LPA) is a ubiquitous lysophospholipid and one of the main membrane-derived lipid signaling molecules. LPA acts as an autocrine/paracrine messenger through at least six G protein-coupled receptors (GPCRs), known as LPA _1–6, to induce various cellular processes including wound healing, differentiation, proliferation, migration, and survival. LPA receptors and autotaxin (ATX), a secreted phosphodiesterase that produces this phospholipid, are overexpressed in many cancers and impact several features of the disease, including cancer-related inflammation, development, and progression. Many ongoing studies aim to understand ATX-LPA axis signaling in cancer and its potential as a therapeutic target. In this review, we discuss the evidence linking LPA signaling to cancer-related inflammation and its impact on cancer progression.

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Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer.

Jie Liang, Masayuki Nagahashi, Eugene Kim … (2013)

Inflammatory bowel disease is an important risk factor for colorectal cancer. We show that sphingosine-1-phosphate (S1P) produced by upregulation of sphingosine kinase 1 (SphK1) links chronic intestinal inflammation to colitis-associated cancer (CAC) and both are exacerbated by deletion of Sphk2. S1P is essential for production of the multifunctional NF-κB-regulated cytokine IL-6, persistent activation of the transcription factor STAT3, and consequent upregulation of the S1P receptor, S1PR1. The prodrug FTY720 decreased SphK1 and S1PR1 expression and eliminated the NF-κB/IL-6/STAT3 amplification cascade and development of CAC, even in Sphk2(-/-) mice, and may be useful in treating colon cancer in individuals with ulcerative colitis. Thus, the SphK1/S1P/S1PR1 axis is at the nexus between NF-κB and STAT3 and connects chronic inflammation and CAC. Copyright © 2013 Elsevier Inc. All rights reserved.

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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

Contributors

Aliesha González-Arenas:

ORCID: http://orcid.org/0000-0002-9506-3180

Journal

Journal ID (nlm-ta): Mediators Inflamm

Journal ID (iso-abbrev): Mediators Inflamm

Journal ID (publisher-id): MI

Title: Mediators of Inflammation

Publisher: Hindawi

ISSN (Print): 0962-9351

ISSN (Electronic): 1466-1861

Publication date (Print): 2017

Publication date (Electronic): 21 December 2017

Volume: 2017

Electronic Location Identifier: 9173090

Affiliations

Departamento de Medicina Genómica y Toxicología Ambiental, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México, Ciudad Universitaria, Coyoacán, 04510 Ciudad de México, Mexico

Author notes

Academic Editor: Santiago Partida-Sanchez

Author information

Silvia Anahi Valdés-Rives http://orcid.org/0000-0002-2104-4884

Aliesha González-Arenas http://orcid.org/0000-0002-9506-3180

Article

DOI: 10.1155/2017/9173090

PMC ID: 5753009

PubMed ID: 29430083

SO-VID: a430990e-7f58-49f0-929d-0d22bf92f1c7

License:

This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

History

Date received : 8 September 2017

Date accepted : 22 November 2017

Funding

Funded by: Consejo Nacional de Ciencia y Tecnología

Award ID: 582548

Funded by: UNAM-PAPIIT

Award ID: IA200718

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Autotaxin-Lysophosphatidic Acid: From Inflammation to Cancer Development

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Cancer Immunotherapy

Most cited references 124

Sphingosine-1-phosphate links persistent STAT3 activation, chronic intestinal inflammation, and development of colitis-associated cancer.

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

Identification of human plasma lysophospholipase D, a lysophosphatidic acid-producing enzyme, as autotaxin, a multifunctional phosphodiesterase.

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