Regulation of autotaxin expression and secretion by lysophosphatidate and sphingosine 1-phosphate

Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer. Autotaxin (ATX) is a secreted enzyme, which produces extracellular lysophosphatidate (LPA) from lysophosphatidylcholine (LPC). LPA activates six G protein-coupled receptors and this is essential for vasculogenesis during embryonic development. ATX is also involved in wound healing and inflammation, and in tumor growth, metastasis, and chemo-resistance. It is, therefore, important to understand how ATX is regulated. It was proposed that ATX activity is inhibited by its product LPA, or a related lipid called sphingosine 1-phosphate (S1P). We now show that this apparent inhibition is ineffective at the high concentrations of LPC that occur in vivo. Instead, feedback regulation by LPA and S1P is mediated by inhibition of ATX expression resulting from phosphatidylinositol-3-kinase activation. Inhibiting ATX activity in mice with ONO-8430506 severely decreased plasma LPA concentrations and increased ATX mRNA in adipose tissue, which is a major site of ATX production. Consequently, the amount of inhibitor-bound ATX protein in the plasma increased. We, therefore, demonstrate the concept that accumulation of LPA in the circulation decreases ATX production. However, this feedback regulation can be overcome by the inflammatory cytokines, TNF-α or interleukin 1β. This enables high LPA and ATX levels to coexist in inflammatory conditions. The results are discussed in terms of ATX regulation in wound healing and cancer. Autotaxin (ATX) is a secreted enzyme, which converts extracellular lysophosphatidylcholine (LPC) into lyso­phosphatidate (LPA). This is an important reaction in cell signaling because LPA activates at least six G protein-coupled receptors to increase cell division, survival, and migration (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar, 2.Brindley D.N. Lin F.T. Tigyi G.J. Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy.Biochim. Biophys. Acta. 2013; 1831: 74-85Crossref PubMed Scopus (95) Google Scholar). ATX serves an essential function in embryonic development because ATX knockout mice die in utero at day 9.5 with defects in vasculogenesis and the development of the neural crest (3.van Meeteren L.A. Ruurs P. Stortelers C. Bouwman P. van Rooijen M.A. Pradere J.P. Pettit T.R. Wakelam M.J. Saulnier-Blache J.S. Mummery C.L. et al.Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.Mol. Cell. Biol. 2006; 26: 5015-5022Crossref PubMed Scopus (448) Google Scholar, 4.Koike S. Keino-Masu K. Masu M. Deficiency of autotaxin/lysophospholipase D results in head cavity formation in mouse embryos through the LPA receptor-Rho-ROCK pathway.Biochem. Biophys. Res. Commun. 2010; 400: 66-71Crossref PubMed Scopus (25) Google Scholar, 5.Koike S. Keino-Masu K. Ohto T. Sugiyama F. Takahashi S. Masu M. Autotaxin/lysophospholipase D-mediated lysophosphatidic acid signaling is required to form distinctive large lysosomes in the visceral endoderm cells of the mouse yolk sac.J. Biol. Chem. 2009; 284: 33561-33570Abstract Full Text Full Text PDF PubMed Scopus (41) Google Scholar, 6.Koike S. Yutoh Y. Keino-Masu K. Noji S. Masu M. Ohuchi H. Autotaxin is required for the cranial neural tube closure and establishment of the midbrain-hindbrain boundary during mouse development.Dev. Dyn. 2011; 240: 413-421Crossref PubMed Scopus (30) Google Scholar). In the postnatal organism, the major function of ATX appears to be in wound healing. ATX is produced in response to inflammation to mediate wound repair. If the inflammation is not resolved, then high ATX concentrations persist in asso­ciation with inflammatory diseases such as arthritis and inflammatory bowel disease (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar, 7.Nikitopoulou I. Oikonomou N. Karouzakis E. Sevastou I. Nikolaidou-Katsaridou N. Zhao Z. Mersinias V. Armaka M. Xu Y. Masu M. et al.Autotaxin expression from synovial fibroblasts is essential for the pathogenesis of modeled arthritis.J. Exp. Med. 2012; 209: 925-933Crossref PubMed Scopus (124) Google Scholar, 8.Hozumi H. Hokari R. Kurihara C. Narimatsu K. Sato H. Sato S. Ueda T. Higashiyama M. Okada Y. Watanabe C. et al.Involvement of autotaxin/lysophospholipase D expression in intestinal vessels in aggravation of intestinal damage through lymphocyte migration.Lab. Invest. 2013; 93: 508-519Crossref PubMed Scopus (36) Google Scholar). In addition, inflammatory bowel disease and hepatitis can progress to carcinogenesis in these organs (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar). Significantly, increased ATX activity is associated with the growth of breast tumors (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar, 10.Teo K. Brunton V.G. The role and of the autotaxin-lysophosphatidate axis in breast J. 2014; PubMed Scopus Google and the ATX is the in cancer N. M. V. H. M. of associated with metastasis of in cell Res. Google Scholar). LPA by ATX activity with ONO-8430506 decreases the of breast tumor growth and metastasis by in mice (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar, Tang X. Dewald J. McMullen Brindley D.N. signaling and the expression of involved in resistance and for cancer J. PubMed Scopus Google Scholar). the lipid activity in cancer cells as to increase LPA in the tumor and LPA signaling decreased breast tumor growth and metastasis in mice by X. Dewald J. Zhao Y.Y. N. Curtis J.M. McMullen Brindley D.N. expression in cancer cells tumor growth and metastasis in Res. 2014; Full Text Full Text PDF PubMed Scopus Google Scholar). the of ATX in cell signaling in and conditions. Consequently, is important to understand how ATX activity and signaling by LPA are regulated. The the role of ATX and how its expression is LPA with a of in the circulation A. C. V. Brindley D.N. extracellular lysophosphatidic acid in J. 2009; PubMed Scopus Google Scholar, A. van Meeteren L.A. M. van K. van et of autotaxin of LPA in the 2010; PubMed Scopus Google Scholar). LPA concentrations are by the of ATX activity LPA by the of a of Brindley D.N. in a lipid and 2012; PubMed Scopus Google Scholar, D.N. C. and Res. 2009; Full Text Full Text PDF PubMed Scopus Google Scholar). Consequently, expression in mice increased the LPA A. C. V. Brindley D.N. extracellular lysophosphatidic acid in J. 2009; PubMed Scopus Google Scholar). for the regulation of the concentrations of extracellular LPA is that ATX activity is by a product feedback inhibition from LPA or its sphingosine 1-phosphate (S1P). This is ATX activity was with concentrations of Meeteren L.A. Ruurs P. E. H. K. A. T. of autotaxin by lysophosphatidic acid and sphingosine Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, of autotaxin and a for lysophosphatidic acid Biol. Chem. 2011; Full Text Full Text PDF PubMed Scopus (25) Google Scholar). This was also to LPA as ATX and of of autotaxin Med. Chem. Lett. 2010; PubMed Scopus Google Scholar, P. S. and of as autotaxin (ATX) Med. Chem. Lett. PubMed Scopus Google Scholar, E. E. P. A. The of and of activity Med. Chem. Lett. 2012; PubMed Scopus Google Scholar, H. Xu X. J. R. Y. J. Tigyi et activity lysophosphatidic acid breast cancer cell migration in and tumor in Res. 2009; PubMed Scopus Google Scholar). We the inhibition of ATX with LPA and S1P because these are with the (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar). LPC concentrations in mice and are in the of D.N. Lin F.T. Tigyi G.J. Role of the autotaxin-lysophosphatidate axis in cancer resistance to chemotherapy and radiotherapy.Biochim. Biophys. Acta. 2013; 1831: 74-85Crossref PubMed Scopus (95) Google Scholar, K. K. J. LPA with 2010; PubMed Scopus Google Scholar). concentrations are high with of in the ATX (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar, A. into how to and a lipid Biol. 2011; PubMed Scopus Google Scholar). that LPA and S1P inhibition of ATX activity in the for ATX is to the However, show that ATX activity is by feedback from LPA and that this the of ATX in cancer cells and adipose This feedback regulation the mRNA concentrations for ATX and ATX a ATX This of feedback regulation is overcome by inflammatory cytokines, which ATX activity and LPA concentrations can be increased in inflammation and cancer. and from ATX was from was from was to by with of and then at The was then and the was through and ATX from and from was a from and N. of is by lipid and is Biol. Chem. Full Text Full Text PDF PubMed Scopus Google Scholar, C. Dewald J. A. I. Tigyi V. Brindley D.N. migration by Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). TNF-α and interleukin from ONO-8430506 was from T. S. Ohhata A. Sugiyama T. 2012; Google Scholar, H. Ohhata A. A. M. Maeda T. H. Y. Y. H. N. et produces decreases in plasma lysophosphatidic acid formation in and 2014; PubMed Scopus Google a was from N. Pradere J.P. P. A. A. A. M. M. M. et a of and as a Exp. PubMed Scopus Google Scholar). was a from T. J. T. L.A. of the tumor a with Biol. Chem. Full Text PDF PubMed Google Scholar). from cancer cells and cells from and in with and at and at cells in and then with and or with was for for or for ATX In cells in with or for of LPA or S1P to with In with was with TNF-α and at a of was at the in and LPA, and ATX at the in was to of ATX protein and of or for a of ATX protein concentrations of and to demonstrate that the activity results to at for at and the as N. Brindley D.N. of autotaxin or activity migration of breast cancer and 2009; PubMed Scopus Google Scholar). ATX inhibition of mouse or was to of of ONO-8430506 and of for of during the to protein as by the protein the of ATX protein was with of and of or S1P or for a of for at and (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). ATX concentrations of and to demonstrate that the activity results to ATX activity in mouse plasma was also in the as (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). mice from and and as (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). in with the of as by the of ONO-8430506 was at in and to for to (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar, H. Ohhata A. A. M. Maeda T. H. Y. Y. H. N. et produces decreases in plasma lysophosphatidic acid formation in and 2014; PubMed Scopus Google Scholar). The was through a to then with or ONO-8430506 a day for at the and as (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). tumor mice or with breast cancer cells into the and as (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). concentrations of LPA and S1P by as (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). was from cell the or from mouse adipose in the the was with and and was then N. Brindley D.N. of autotaxin or activity migration of breast cancer and 2009; PubMed Scopus Google Scholar). expression was to the or in expression of ATX mRNA the with and results are to from that and mouse ATX and and and ATX protein in mouse plasma was by as and by (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). ATX protein was from of cell the ATX from to the ATX protein was then to the of and protein from cell by the protein plasma TNF-α concentrations by the are as the from at least The for or the with a for or to for was for and results The that LPA and S1P feedback regulation ATX activity was by which is an of LPC that a product by ATX of autotaxin and a for lysophosphatidic acid Biol. 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Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). ONO-8430506 of the activity However, in the apparent activity not by and be to ATX and also LPC in to LPA and LPC ATX activity in the We, therefore, to this the inhibition by and this increased the activity by The concept that LPA a feedback regulation ATX is an and this at the of ATX We, therefore, cancer cells and which high of to this of LPA or S1P to decreased ATX mRNA expression We also this of LPA and S1P ATX protein by with increased mRNA concentrations for ATX with in ATX mRNA expression was by LPA or S1P to the and these by a LPA H. Sato K. N. A. E. J. T. M. Y. Watanabe T. et a for lysophosphatidic acid PubMed Scopus Google and by a S1P 1-phosphate as Biol. Chem. Full Text Full Text PDF PubMed Scopus Google in ATX mRNA expression also the was with is by lipid and is Biol. Chem. Full Text Full Text PDF PubMed Scopus Google a or a S. A. N. et 1-phosphate tumor to in Biol. PubMed Scopus Google results that LPA and S1P signaling the expression of and S1P ATX mRNA expression through LPA and S1P of cells in or in the of LPA or or of the LPA or S1P ATX mRNA expression increased in cells in with of the LPA or ATX mRNA levels in cells in ATX mRNA expression increased in cells in with or ATX mRNA levels in cells in are from increase in ATX mRNA with in ATX mRNA with The of LPA and S1P in mRNA for ATX by of and Inhibiting or protein with or or decreases in ATX mRNA not We also the of ATX by cancer cells and cells a feedback ATX production. in with to the concentrations of mRNA for ATX and with This decreased ATX mRNA an that was by ATX activity with ONO-8430506 or that these ATX mRNA in the of or in the of LPA The of mRNA concentrations for ATX by LPA and LPC by decreased of ATX from the cells Inhibiting ATX activity with ONO-8430506 or these of The role of ATX in its expression was also in by mice for with This decreased the activity of ATX as in the plasma (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google by and this was by a of in LPA concentrations S1P concentrations not by ONO-8430506 as from (9.Benesch M.G.K. Tang X. Maeda T. Ohhata A. Zhao Y.Y. Kok B.P.C. Dewald J. Hitt M. Curtis J.M. McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google Scholar). is a major of ATX in the circulation J. J.P. S. C. C. et of resistance in of lysophospholipase PubMed Scopus Google Scholar, R. C. S. E. A. C. van Meeteren L.A. P. Saulnier-Blache J.S. of autotaxin and plasma lysophosphatidic Res. 2011; Full Text Full Text PDF PubMed Scopus Google Scholar, R. C. S. E. A. C. van Meeteren L.A. P. 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McMullen T.P.W. et al.Inhibition of autotaxin delays breast tumor growth and lung metastasis in mice.FASEB J. 2014; 28: 2655-2666Crossref PubMed Scopus (85) Google mice with breast tumors at day plasma ATX levels mice also the plasma LPA concentrations of mice cancer S1P concentrations not The mice also plasma levels of the TNF-α these proposed that inflammatory the inhibition of ATX mRNA expression by LPA and of cells with TNF-α or or in increased ATX mRNA TNF-α or also the inhibition ATX mRNA expression by LPA or S1P We from results that the product inhibition of ATX by LPA and S1P is an of the and that is to This also for ATX because concentrations of are to of or the of S. van A. J. van P. H. of an for 2010; PubMed Scopus Google Scholar, M. T. S. H. R. H. J. T. and of autotaxin a Chem. Biol. 2013; PubMed Scopus Google Scholar, J. A. K. E. T. A. M. 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Acta. 2011; PubMed Scopus Google now this ATX activity are from the are to occur are to ATX activity in from cell N. Brindley D.N. of autotaxin or activity migration of breast cancer and 2009; PubMed Scopus Google Scholar, Y. J. J. Y. Y. R. E. R. et al.Autotaxin and and receptors in tumor cells the in and Res. PubMed Scopus Google Scholar, M. cell in 2011; PubMed Scopus Google Scholar). This can from the of by the cells or the of to the We demonstrate that the of concentrations of can the because concentrations of LPA, and S1P can ATX activity as with to be in these to cell be We also from that of through and receptors decreases the expression of mRNA for LPA from LPC by therefore, as a feedback of ATX mRNA production. This feedback can be in by ATX activity and LPA The the of the secreted ATX LPA from LPC in this feedback other at LPA and S1P ATX ATX mRNA expression levels not in other cell with LPA or as by cancer mouse embryonic and embryonic cells C. 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The by which ATX its by LPA concentrations is of a feedback It is, therefore, that a ATX increase ATX In such an increase can as a of the of the In this feedback S1P concentrations not by ATX This is not as ATX mice the levels of plasma LPA with S1P levels are not (3.van Meeteren L.A. Ruurs P. Stortelers C. Bouwman P. van Rooijen M.A. Pradere J.P. Pettit T.R. Wakelam M.J. Saulnier-Blache J.S. Mummery C.L. et al.Autotaxin, a secreted lysophospholipase D, is essential for blood vessel formation during development.Mol. Cell. Biol. 2006; 26: 5015-5022Crossref PubMed Scopus (448) Google Scholar, M. S. Y. R. S. M. Noji S. Y. J. H. Autotaxin blood vessels and is required for embryonic by lysophosphatidic Biol. Chem. 2006; Full Text Full Text PDF PubMed Scopus Google Scholar). This that ATX is not a major of S1P concentrations in vivo. However, not S1P as a of ATX expression in and are We also that the of LPA from are and that LPA concentrations decreased the ATX This also the regulation of ATX expression during wound inflammation, and cancer. We in plasma ATX activity and LPA concentrations in mice with breast tumors with increased plasma TNF-α We that of the cytokines, TNF-α overcome of ATX We also demonstrate in that ATX expression can be increased to levels by other inflammatory and results that signaling is with to the regulation of ATX expression and that of an is to a results from cell are with the that the of inflammatory cytokines, such as TNF-α and in and is a for increased ATX expression and the for LPA to the wound (1.Benesch M.G.K. Ko Y.M. McMullen T.P.W. Brindley D.N. Autotaxin in the crosshairs: Taking aim at cancer and other inflammatory conditions.FEBS Lett. 2014; 588: 2712-2727Crossref PubMed Scopus (87) Google Scholar, D.N. and related signaling in cell division, and Cell. 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