Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo.

G.K Matthew,Tang Xiaoyun,Venkatraman Ganesh,N David,T Raie

doi:10.7555/jbr.30.20150058

Abstract

Extracellular lysophosphatidate (LPA) is a potent bioactive lipid that signals through six G-protein-coupled receptors. This signaling is required for embryogenesis, tissue repair and remodeling processes. LPA is produced from circulating lysophosphatidylcholine by autotaxin (ATX), and is degraded outside cells by a family of three enzymes called the lipid phosphate phosphatases (LPPs). In many pathological conditions, particularly in cancers, LPA concentrations are increased due to high ATX expression and low LPP activity. In cancers, LPA signaling drives tumor growth, angiogenesis, metastasis, resistance to chemotherapy and decreased efficacy of radiotherapy. Hence, targeting the ATX-LPA-LPP axis is an attractive strategy for introducing novel adjuvant therapeutic options. In this review, we will summarize current progress in targeting the ATX-LPA-LPP axis with inhibitors of autotaxin activity, LPA receptor antagonists, LPA monoclonal antibodies, and increasing low LPP expression. Some of these agents are already in clinical trials and have applications beyond cancer, including chronic inflammatory diseases.

Highlights

As the simplest phospholipid, lysophosphatidate (LPA) is by no means a simple biological molecule
We recently showed that ATX expression is negatively regulated by LPA signaling through increased phosphatidylinositol 3-kinase (PI3K); this inhibition is overcome by pro-inflammatory cytokines[55]
We showed that overexpression of LPP1 in breast and thyroid cancer cell lines decreases tumor growth and metastasis by up to 80% compared with the expression of catalytically inactive LPP1 in both syngeneic and xenograft mouse models[116] (Table 1)

Summary

Introduction

Lysophosphatidate (LPA) is by no means a simple biological molecule. Extracellular LPA, via signaling through at least six G-protein-coupled receptors, mediates a plethora of physiological and pathological processes including embryogenesis, wound healing, chronic inflammatory diseases, and cancer progression and therapy resistance. ATX protein expression is increased leading to higher LPA levels in many different tumors.

Results

Conclusion