title: Recent advances in targeting the autotaxin-lysophosphatidate-lipid phosphate phosphatase axis in vivo.
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.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
authors.forename: Ganesh
authors.initials: G
authors.lastname: Venkatraman
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada.
authors.forename: Raie T
authors.initials: RT
authors.lastname: Bekele
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, T6G 2S2, Canada. david.brindley@ualberta.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
keywords: cancer; chronic inflammation; cytokines; monoclonal antibodies; wound repair