Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions. Issue 16 (19th February 2014)

• Record Type: Journal Article
• Authors: Benesch, Matthew G.K.; Ko, Yi M.; McMullen, Todd P.W.; Brindley, David N.
• Is Part Of: FEBS letters. Volume 588:Issue 16(2014)
• Page Start: 2712
• Page End: 2727
• Publication Date: 2014-02-19
• Subjects: ATX -- autotaxin -- BALF -- bronchoalveolar lavage fluid -- C18:0 etc -- indicates the numbers of carbon atoms in a fatty acid and the number of double bonds -- COX-2 -- cyclooxygenase-2 -- ENPP2 -- ecto-nucleotide pyrophosphatase/phosphodiesterase family member 2 -- EGF -- epidermal growth factor -- HCC -- hepatocellular carcinoma -- IC50 -- inhibitory concentration of 50% -- GM-CSF -- granulocyte macrophage colony-stimulating factor -- IL -- interleukin -- IPF -- idiopathic pulmonary fibrosis -- Ki -- binding affinity -- LPA -- lysophosphatidate -- LPC -- lysophosphatidylcholine -- lysoPLD -- lysophospholipase D -- LPA1-6 -- LPA receptors 1-6 -- LPAR -- LPA receptors (in general) -- LPPs -- lipid phosphate phosphatases -- KO -- knockout -- NSAID -- Non-steroidal anti-inflammatory drug -- PA -- phosphatidate -- Th1 or 2 -- T helper cell type 1 or 2 -- PDGF -- platelet-derived growth factor -- TNF-α -- tumor necrosis factor alpha -- VEGF -- vascular endothelial growth factor -- Autotaxin inhibition -- Lysophosphatidate -- Inflammation -- Cytokine -- Tumor microenvironment -- Wound healing; Biochemistry -- Periodicals; Biophysics -- Periodicals; Molecular biology -- Periodicals; Biochimie -- Périodiques; Biochemistry; Biophysics; Molecular biology; Periodicals; 572.05
• DOI: 10.1016/j.febslet.2014.02.009
• Languages: English
• ISSNs: 0014-5793

Abstract

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.