title: Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions.
abstract: Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in blood plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through at least six G-protein coupled receptors to promote cell survival, proliferation and migration. The autotaxin/lysophosphatidate signaling axis is involved in wound healing and tissue remodeling, and it drives many chronic inflammatory conditions from fibrosis to colitis, asthma and cancer. In cancer, lysophosphatidate signaling promotes resistance to chemotherapy and radiotherapy, and increases both angiogenesis and metastasis. Research into autotaxin inhibitors is accelerating, both as primary and adjuvant therapy. Historically, autotaxin inhibitors had poor bioavailability profiles and thus had limited efficacy in vivo. This situation is now changing, especially since the recent crystal structure of autotaxin is now enabling rational inhibitor design. In this review, we will summarize current knowledge on autotaxin-mediated disease processes including cancer, and discuss recent advancements in the development of autotaxin-targeting strategies. We will also provide new insights into autotaxin as an inflammatory mediator in the tumor microenvironment that promotes cancer progression and therapy resistance.
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada.
authors.forename: Matthew G K
authors.initials: MG
authors.lastname: Benesch
authors.affiliation: Department of Surgery, University of Alberta, 2D4.41 WC Mackenzie Health Science Centre, Edmonton, Alberta T6G 2R7, Canada.
authors.forename: Yi M
authors.initials: YM
authors.lastname: Ko
authors.affiliation: Department of Surgery, University of Alberta, 2D4.41 WC Mackenzie Health Science Centre, Edmonton, Alberta T6G 2R7, Canada.
authors.forename: Todd P W
authors.initials: TP
authors.lastname: McMullen
authors.affiliation: Signal Transduction Research Group, Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2S2, Canada. Electronic address: david.brindley@ualberta.ca.
authors.forename: David N
authors.initials: DN
authors.lastname: Brindley
mesh_terms: D000818:Animals; D055808:Drug Discovery; D047108:Embryonic Development; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006801:Humans; D007249:Inflammation / Q000188:drug therapy / Q000201:enzymology; D009369:Neoplasms / Q000188:drug therapy / Q000201:enzymology*; D010727:Phosphoric Diester Hydrolases / Q000378:metabolism*; D000099189:Lysophospholipase D
chemical_list: D004791:Enzyme Inhibitors; D010727:Phosphoric Diester Hydrolases; D000099189:Lysophospholipase D
keywords: Autotaxin inhibition; Cytokine; Inflammation; Lysophosphatidate; Tumor microenvironment; Wound healing