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Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions
Author(s) -
Benesch Matthew G.K.,
Ko Yi M.,
McMullen Todd P.W.,
Brindley David N.
Publication year - 2014
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1016/j.febslet.2014.02.009
Subject(s) - autotaxin , cancer research , cancer , biology , cancer cell , angiogenesis , lysophosphatidylcholine , signal transduction , metastasis , medicine , microbiology and biotechnology , pharmacology , lysophosphatidic acid , receptor , biochemistry , phospholipid , membrane , phosphatidylcholine
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.