Elsevier

Progress in Lipid Research

Volume 58, April 2015, Pages 76-96
Progress in Lipid Research

Review
Autotaxin, a secreted lysophospholipase D, as a promising therapeutic target in chronic inflammation and cancer

https://doi.org/10.1016/j.plipres.2015.02.001Get rights and content

Abstract

Autotaxin (ATX) is a member of the nucleotide pyrophosphatase/phosphodiesterase family of ectoenzymes that hydrolyzes phosphodiester bonds of various nucleotides. It possesses lysophospholipase D activity, catalyzing the hydrolysis of lysophosphatidylcholine into lysophosphatidic acid (LPA), and it is considered the major LPA-producing enzyme in the circulation. LPA is a bioactive phospholipid with diverse functions in almost every mammalian cell type, which exerts its action through binding to specific G protein-coupled receptors and stimulates various cellular functions, including migration, proliferation and survival. As a consequence, both ATX and LPA have attracted the interest of researchers, in an effort to understand their roles in physiology and pathophysiology. The present review article aims to summarize the existing knowledge as to the implications of ATX in chronic inflammatory diseases and cancer and to highlight the low molecular weight compounds, which have been developed as leads for the discovery of novel medicines to treat inflammatory diseases and cancer.

Introduction

Autotaxin (ATX), originally isolated in 1992 [1] is a member of the nucleotide pyrophosphatase/phosphodiesterase family of ectoenzymes that hydrolyses phosphodiester bonds of various nucleotides [2], and it is also known as ectonucleotide pyrophosphatase/phosphodiesterase 2 (ENPP2 or NPP2). ATX possesses lysophospholipase D activity, catalyzing the hydrolysis of lysophosphatidylcholine (LPC, 1) into lysophosphatidic acid (LPA, 2) and choline (3) (Fig. 1) [3]. LPA is a bioactive phospholipid with diverse functions in almost every mammalian cell type, which exerts its action through binding to specific G protein-coupled receptors (GPCRs, specifically LPAR1-6 in mammals) [4], [5], [6] and stimulates various cellular functions, including migration, proliferation and survival. Both ATX and LPA have attracted the interest of researchers in an effort to understand their roles in pathophysiology and to develop new agents to treat several pathological conditions, as has been discussed in various review articles [7], [8], [9], [10], [11], [12]. The aim of this review article is to summarize the existing knowledge as to the implications of ATX in chronic inflammatory diseases and cancer and to highlight the low molecular weight compounds, which have been developed as leads for the discovery of novel drugs.

Section snippets

Isoforms, structure and catalytic mechanism

ATX, a ∼125 kDa enzyme, is the best-characterized member of the nucleotide pyrophosphatase-/phosphodiesterase (ENPP) family, which consists of two main subgroups – namely ENPP1-3 and ENPP4-7 [2]. It is secreted as a constitutively catalytically active glycoprotein [13], [14], while the other ENPPs are transmembrane or anchored proteins. ATX is the only member that exhibits extracellular lysophospholipase D (lysoPLD) activity and participates in LPA signaling.

The cDNA cloning of ATX in 1994 [15],

Embryonic development

ATX is first expressed at the floor plate of the neural tube at embryonic day E9.5 [49], [50], following the expression (E8.5) of most LPA receptors at neural headfolds, forebrain and hindbrain [51], [52]. Complete genetic deletion of ATX in mice results in aberrant vascular and neuronal development leading to embryonic lethality at E9.5 [53], [54]. Similar conclusions on the role of ATX in both vascular and neural development have been obtained by studies in zebrafish [55], [56]. Therefore,

ATX in chronic inflammation

The first indications on a possible involvement of ATX in chronic inflammatory disorders appeared by the observation of increased ATX expression in the cerebrospinal fluid of multiple sclerosis patients [70], in the frontal cortex of Alzheimer-like dementia patients [91], in reactive astrocytes after trauma [92], in endothelial cells of HEVs upon chronic inflammation [93], in the fibrotic lung [74] and in the arthritic synovium [76]. Accordingly tumor necrosis factor (TNF), the major

ATX in cancer

As exemplified by the association between chronic inflammatory bowel diseases and the increased risk of colon carcinoma, able evidence suggests that chronic inflammation can predispose to cancer. Although the study of ATX/LPA in cancer has preceded studies in inflammation, the discovery of the role of ATX/LPA in chronic inflammation adds an additional layer to the multi effects of the axis in cancer development.

Chemical inhibition

Because of its implication in various pathological conditions such as cancer, chronic inflammation and fibrotic diseases, ATX is being actively pursued as an attractive medicinal target. As a consequence, a variety of synthetic chemical inhibitors have been designed and developed in both academia and pharmaceutical industry. The various chemical classes of inhibitors have been summarized in a number of review articles [11], [245], [246], [247], [248], [249]. After the discovery that LPAs and

Concluding remarks

ATX is a secreted lysophospholipase D widely present in biological fluids catalyzing the production of LPA, a growth factor-like lysophospholipid with pleiotropic effects in almost all cell types. ATX was originally isolated from the supernatant of melanoma cells as an autocrine motility factor; since, increased ATX expression has been detected in a variety of cancers and cancer cell lines, and its transgenic overexpression in the mammary gland led to spontaneous breast cancer in aged mice. ATX

Acknowledgements

The present work was funded by a National SYNERGASIA 2009 Grant (Project Code 09SYN-11-679), co-funded by the European Regional Development Fund and National resources through the Operational Program “Competitiveness and Entrepreneurship” of the National Strategic Reference Framework (NSRF). We are thankful to N. Xylourgidis for the realization of Fig. 4.

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