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Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions

Authors
  • Benesch, Matthew G.K.
  • Ko, Yi M.
  • McMullen, Todd P.W.
  • Brindley, David N.1, 2, 3, 4, 3, 5
  • 1 Signal Transduction Research Group
  • 2 Department of Biochemistry
  • 3 University of Alberta
  • 4 Department of Surgery
  • 5 2D4.41 WC Mackenzie Health Science Centre
Type
Published Article
Journal
FEBS Letters
Publisher
Wiley (John Wiley & Sons)
Publication Date
Jan 01, 2014
Accepted Date
Feb 12, 2014
Identifiers
DOI: 10.1016/j.febslet.2014.02.009
Source
Elsevier
Keywords
License
Unknown

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.

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