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David N. Brindley - One of the best experts on this subject based on the ideXlab platform.

  • Dexamethasone Attenuates X-Ray-Induced Activation of the Autotaxin-Lysophosphatidate-Inflammatory Cycle in Breast Tissue and Subsequent Breast Fibrosis.
    Cancers, 2020
    Co-Authors: Guanmin Meng, Todd P. W. Mcmullen, Xiaoyun Tang, Melinda Wuest, Jennifer Dufour, Frank Wuest, David Murray, David N. Brindley
    Abstract:

    We recently showed that radiation-induced DNA damage in breast adipose tissue increases Autotaxin secretion, production of lysophosphatidate (LPA) and expression of LPA1/2 receptors. We also established that dexamethasone decreases Autotaxin production and LPA signaling in non-irradiated adipose tissue. In the present study, we showed that dexamethasone attenuated the radiation-induced increases in Autotaxin activity and the concentrations of inflammatory mediators in cultured human adipose tissue. We also exposed a breast fat pad in mice to three daily 7.5 Gy fractions of X-rays. Dexamethasone attenuated radiation-induced increases in Autotaxin activity in plasma and mammary adipose tissue and LPA1 receptor levels in adipose tissue after 48 h. DEX treatment during five daily fractions of 7.5 Gy attenuated fibrosis by ~70% in the mammary fat pad and underlying lungs at 7 weeks after radiotherapy. This was accompanied by decreases in CXCL2, active TGF-β1, CTGF and Nrf2 at 7 weeks in adipose tissue of dexamethasone-treated mice. Autotaxin was located at the sites of fibrosis in breast tissue and in the underlying lungs. Consequently, our work supports the premise that increased Autotaxin production and lysophosphatidate signaling contribute to radiotherapy-induced breast fibrosis and that dexamethasone attenuated the development of fibrosis in part by blocking this process.

  • Autotaxin and Breast Cancer: Towards Overcoming Treatment Barriers and Sequelae
    Cancers, 2020
    Co-Authors: Matthew G.k. Benesch, Xiaoyun Tang, David N. Brindley
    Abstract:

    After a decade of intense preclinical investigations, the first in-class Autotaxin inhibitor, GLPG1690, has entered Phase III clinical trials for idiopathic pulmonary fibrosis. In the intervening time, a deeper understanding of the role of the Autotaxin–lysophosphatidate (LPA)–lipid phosphate phosphatase axis in breast cancer progression and treatment resistance has emerged. Concordantly, appreciation of the tumor microenvironment and chronic inflammation in cancer biology has matured. The role of LPA as a central mediator behind these concepts has been exemplified within the breast cancer field. In this review, we will summarize current challenges in breast cancer therapy and delineate how blocking LPA signaling could provide novel adjuvant therapeutic options for overcoming therapy resistance and adverse side effects, including radiation-induced fibrosis. The advent of Autotaxin inhibitors in clinical practice could herald their applications as adjuvant therapies to improve the therapeutic indexes of existing treatments for breast and other cancers.

  • Coming of Age for Autotaxin and Lysophosphatidate Signaling: Clinical Applications for Preventing, Detecting and Targeting Tumor-Promoting Inflammation.
    Cancers, 2018
    Co-Authors: Matthew G.k. Benesch, Todd P. W. Mcmullen, Iain T. K. Macintyre, David N. Brindley
    Abstract:

    A quarter-century after the discovery of Autotaxin in cell culture, the Autotaxin-lysophosphatidate (LPA)-lipid phosphate phosphatase axis is now a promising clinical target for treating chronic inflammatory conditions, mitigating fibrosis progression, and improving the efficacy of existing cancer chemotherapies and radiotherapy. Nearly half of the literature on this axis has been published during the last five years. In cancer biology, LPA signaling is increasingly being recognized as a central mediator of the progression of chronic inflammation in the establishment of a tumor microenvironment which promotes cancer growth, immune evasion, metastasis, and treatment resistance. In this review, we will summarize recent advances made in understanding LPA signaling with respect to chronic inflammation and cancer. We will also provide perspectives on the applications of inhibitors of LPA signaling in preventing cancer initiation, as adjuncts extending the efficacy of current cancer treatments by blocking inflammation caused by either the cancer or the cancer therapy itself, and by disruption of the tumor microenvironment. Overall, LPA, a simple molecule that mediates a plethora of biological effects, can be targeted at its levels of production by Autotaxin, LPA receptors or through LPA degradation by lipid phosphate phosphatases. Drugs for these applications will soon be entering clinical practice.

  • Autotaxin is an inflammatory mediator and therapeutic target in thyroid cancer
    Endocrine-related cancer, 2015
    Co-Authors: Matthew G.k. Benesch, David N. Brindley, Xiaoyun Tang, Yuan Y. Zhao, Jay Dewald, Jonathan M. Curtis, Ana Lopez-campistrous, Raymond Lai, Todd P. W. Mcmullen
    Abstract:

    Autotaxin is a secreted enzyme that converts extracellular lysophosphatidylcholine to lysophosphatidate (LPA). In cancers, LPA increases tumour growth, metastasis and chemoresistance by activating six G-protein coupled receptors. We examined >200 human thyroid biopsies. Autotaxin expression in metastatic deposits and primary carcinomas was four- to tenfold higher than in benign neoplasms or normal thyroid tissue. Autotaxin immunohistochemical staining was also increased in benign neoplasms with leukocytic infiltrations. Malignant tumours were distinguished from benign tumours by high tumour Autotaxin, LPA levels and inflammatory mediators including IL1β, IL6, IL8, GMCSF, TNFα, CCL2, CXCL10 and platelet-derived growth factor (PDGF)-AA. We determined the mechanistic explanation for these results and revealed a vicious regulatory cycle in which LPA increased the secretion of 16 inflammatory modulators in papillary thyroid cancer cultures. Conversely, treating cancer cells with ten inflammatory cytokines and chemokines or PDGF-AA and PDGF-BB increased Autotaxin secretion. We confirmed that this Autotaxin/inflammatory cycle occurs in two SCID mouse models of papillary thyroid cancer by blocking LPA signalling using the Autotaxin inhibitor ONO-8430506. This decreased the levels of 16 inflammatory mediators in the tumours and was accompanied by a 50-60% decrease in tumour volume. This resulted from a decreased mitotic index for the cancer cells and decreased levels of vascular endothelial growth factor and angiogenesis in the tumours. Our results demonstrate that the Autotaxin/inflammatory cycle is a focal point for driving malignant thyroid tumour progression and possibly treatment resistance. Inhibiting Autotaxin activity provides an effective and novel strategy for decreasing the inflammatory phenotype in thyroid carcinomas, which should complement other treatment modalities.

  • Autotaxin in the crosshairs: taking aim at cancer and other inflammatory conditions.
    FEBS letters, 2014
    Co-Authors: Matthew G.k. Benesch, Todd P. W. Mcmullen, David N. Brindley
    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.

Gilles Ferry - One of the best experts on this subject based on the ideXlab platform.

  • Autotaxin
    Cellular and Molecular Life Sciences, 2009
    Co-Authors: Jean A. Boutin, Gilles Ferry
    Abstract:

    Autotaxin is a protein of approximately 900 amino acids discovered in the early 1990s. Over the past 15 years, a strong association between cancer cells and Autotaxin production has been observed. Recent publications indicate that Autotaxin and the capacity of cancer to metastasise are intimately linked. The discovery of new molecular targets in pharmacology is a mixture of pure luck, hard work and industrial strategy. Despite a crucial and desperate need for new therapeutic tools, many targets are approached in oncology, but only a few are validated and end up at the patient bed. Outside the busy domain of kinases, few targets have been discovered that can be useful in treating cancer, particularly metastatic processes. The fortuitous relationship between Autotaxin and lysophosphatidic acid renders the results of observations made in the diabetes/obesity context considerably important. The literature provides observations that may aid in redesigning experiments to validate Autotaxin as a potential oncology target.

  • S32826, a nanomolar inhibitor of Autotaxin: discovery, synthesis and applications as a pharmacological tool.
    The Journal of pharmacology and experimental therapeutics, 2008
    Co-Authors: Gilles Ferry, Adeline Giganti, Natacha Moulharat, Jean-philippe Pradere, Patrice Desos, Anne Try, Annie Genton, Monique Beucher-gaudin, Michel Lonchampt, Marc Bertrand
    Abstract:

    Autotaxin catalyzes the transformation of lyso -phosphatidylcholine in lyso -phosphatidic acid (LPA). LPA is a phospholipid possessing a large panel of activity, in particular as a motility factor or as a growth signal, through its G-protein coupled seven transmembrane receptors. Indirect evidence strongly suggests that Autotaxin is the main, if not the only source of circulating LPA. Because of its central role in pathologic conditions, such as oncology and diabetes/obesity, the biochemical properties of Autotaxin has attracted a lot of attention, but confirmation of its role in pathology remains elusive. One way to validate and/or confirm its central role, is to find potent and selective inhibitors. A systematic screening of several thousand compounds using a colorimetric assay and taking advantage of the phosphodiesterase activity of Autotaxin that requires the enzymatic site than for LPA generation, led to the discovery of a potent nanomolar inhibitor, [4-(tetradecanoylamino)benzyl]phosphonic acid (S32826). This compound was inhibitory toward the various Autotaxin isoforms, using an assay measuring the [ 14 C] lyso -phosphatidylcholine conversion into [ 14 C]LPA. We also evaluated the activity of S32826 in cellular models of diabesity and oncology. Nevertheless, the poor in vivo stability and/or bioavailability of the compound did not permit to use it in animals. S32826 is the first reported inhibitor of Autotaxin with an IC 50 in the nanomolar range that can be used to validate the role of Autotaxin in various pathologies in cellular models.

  • Molecular pharmacology of adipocyte-secreted Autotaxin
    Chemico-biological interactions, 2008
    Co-Authors: Natacha Moulharat, Adeline Giganti, Benjamin Fould, Jean A. Boutin, Gilles Ferry
    Abstract:

    Autotaxin is a type II ecto-nucleotide pyrophosphate phosphodiesterase enzyme. It has been recently discovered that Autotaxin also catalyses a lyso-phospholipase D activity. This enzyme probably provides most of the extracellular lyso-phosphatidic acid from lyso-phosphatidylcholine. There is almost no pharmacological tools available to study Autotaxin. Indeed, all the reported inhibitors, thus far, are uneasy-to-use, lyso-phosphatidic acid derivatives. Initially, Autotaxin was recognized as a phosphodiesterase (NPP2) [Bollen et al., Curr. Rev. Biochem. Biol. 35 (2000) 393-432], based on sequence similarity and enzymatic capability of Autotaxin to catalyse ecto-nucleotidase activity. Phosphodiesterase forms a large family of enzymes characterized by a large number of chemically diverse inhibitors. None of them have been tested on Autotaxin activity. For this reason, we screened those reported inhibitors, as well as a series of compounds, mostly kinase inhibitor-oriented, on Autotaxin activity. Only two compounds of the various phosphodiesterase inhibitors (calmidazolium and vinpocetine) were potent enough to inhibit Autotaxin catalytic activity. From the kinase inhibitor library, we found damnacanthal and hypericin, inhibiting phosphodiesterase activity in the 100-microM range, comparable to most of other available phospholipid-like inhibitors.

  • Potential involvement of adipocyte insulin resistance in obesity-associated up-regulation of adipocyte lysophospholipase D/Autotaxin expression.
    Diabetologia, 2005
    Co-Authors: Jérémie Boucher, Jean Boutin, Gilles Ferry, Didier Quilliot, J. P. Pradères, Marie-françoise Simon, Sandra Grès, Charlotte Guigné, Danielle Prévot, Christian Carpéné
    Abstract:

    AIMS/HYPOTHESIS: Autotaxin is a lysophospholipase D that is secreted by adipocytes and whose expression is substantially up-regulated in obese, diabetic db/db mice. The aim of the present study was to depict the physiopathological and cellular mechanisms involved in regulation of adipocyte Autotaxin expression. METHODS: Autotaxin mRNAs were quantified in adipose tissue from db/db mice (obese and highly diabetic type 2), gold-thioglucose-treated (GTG) mice (highly obese and moderately diabetic type 2), high-fat diet-fed (HFD) mice (obese and moderately diabetic type 2), streptozotocin-treated mice (thin and diabetic type 1), and massively obese humans with glucose intolerance. RESULTS: When compared to non-obese controls, Autotaxin expression in db/db mice was significantly increased, but not in GTG, HFD, or streptozotocin-treated mice. During db/db mice development, up-regulation of Autotaxin occurred only 3 weeks after the emergence of hyperinsulinaemia, and simultaneously with the emergence of hyperglycaaemia. Adipocytes from db/db mice exhibited a stronger impairment of insulin-stimulated glucose uptake than non-obese and HFD-induced obese mice. Autotaxin expression was up-regulated by treatment with TNFalpha (insulin resistance-promoting cytokine), and down-regulated by rosiglitazone treatment (insulin-sensitising compound) in 3T3F442A adipocytes. Finally, adipose tissue Autotaxin expression was significantly up-regulated in patients exhibiting both insulin resistance and impaired glucose tolerance. CONCLUSIONS/INTERPRETATION: The present work demonstrates the existence of a db/db-specific up-regulation of adipocyte Autotaxin expression, which could be related to the severe type 2 diabetes phenotype and adipocyte insulin resistance, rather than excess adiposity in itself. It also showed that type 2 diabetes in humans is also associated with up-regulation of adipocyte Autotaxin expression.

Allan J. B. Watson - One of the best experts on this subject based on the ideXlab platform.

Xianjun Fang - One of the best experts on this subject based on the ideXlab platform.

  • Autotaxin lysopholipase d and lysophosphatidic acid regulate murine hemostasis and thrombosis
    Journal of Biological Chemistry, 2009
    Co-Authors: Zehra Pamuklar, Lorenzo Federico, Makiko Umezugoto, Anping Dong, Manikandan Panchatcharam, Zachary Fulerson, Evgeny V Berdyshev, Viswanathan Natarajan, Xianjun Fang, Laurens A Van Meeteren
    Abstract:

    Abstract The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of Autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50% normal plasma LPA levels, were more prone to thrombosis. Plasma Autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant Autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by Autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of Autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

  • Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis
    The Journal of biological chemistry, 2009
    Co-Authors: Zehra Pamuklar, Shuying Liu, Lorenzo Federico, Anping Dong, Manikandan Panchatcharam, Zachary Fulerson, Evgeny V Berdyshev, Viswanathan Natarajan, Makiko Umezu-goto, Xianjun Fang
    Abstract:

    The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of Autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50% normal plasma LPA levels, were more prone to thrombosis. Plasma Autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant Autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by Autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of Autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

Zehra Pamuklar - One of the best experts on this subject based on the ideXlab platform.

  • Autotaxin lysopholipase d and lysophosphatidic acid regulate murine hemostasis and thrombosis
    Journal of Biological Chemistry, 2009
    Co-Authors: Zehra Pamuklar, Lorenzo Federico, Makiko Umezugoto, Anping Dong, Manikandan Panchatcharam, Zachary Fulerson, Evgeny V Berdyshev, Viswanathan Natarajan, Xianjun Fang, Laurens A Van Meeteren
    Abstract:

    Abstract The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of Autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50% normal plasma LPA levels, were more prone to thrombosis. Plasma Autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant Autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by Autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of Autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

  • Autotaxin/Lysopholipase D and Lysophosphatidic Acid Regulate Murine Hemostasis and Thrombosis
    The Journal of biological chemistry, 2009
    Co-Authors: Zehra Pamuklar, Shuying Liu, Lorenzo Federico, Anping Dong, Manikandan Panchatcharam, Zachary Fulerson, Evgeny V Berdyshev, Viswanathan Natarajan, Makiko Umezu-goto, Xianjun Fang
    Abstract:

    The lipid mediator lysophosphatidic acid (LPA) is a potent regulator of vascular cell function in vitro, but its physiologic role in the cardiovasculature is largely unexplored. To address the role of LPA in regulating platelet function and thrombosis, we investigated the effects of LPA on isolated murine platelets. Although LPA activates platelets from the majority of human donors, we found that treatment of isolated murine platelets with physiologic concentrations of LPA attenuated agonist-induced aggregation. Transgenic overexpression of Autotaxin/lysophospholipase D (Enpp2), the enzyme necessary for production of the bulk of biologically active LPA in plasma, elevated circulating LPA levels and induced a bleeding diathesis and attenuation of thrombosis in mice. Intravascular administration of exogenous LPA recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. Enpp2+/- mice, which have ∼50% normal plasma LPA levels, were more prone to thrombosis. Plasma Autotaxin associated with platelets during aggregation and concentrated in arterial thrombus, and activated but not resting platelets bound recombinant Autotaxin/lysoPLD in an integrin-dependent manner. These results identify a novel pathway in which LPA production by Autotaxin/lysoPLD regulates murine hemostasis and thrombosis and suggest that binding of Autotaxin/lysoPLD to activated platelets may provide a mechanism to localize LPA production.

  • Overexpression of the Plasma Lysophospholipase D Autotaxin Reveals a Novel Pathway for Regulation of Hemostasis in Mice.
    Blood, 2007
    Co-Authors: Lorenzo Federico, Gordon B Mills, Zehra Pamuklar, Andrew J. Morris, Sue Liu, Susan S. Smyth
    Abstract:

    Abstract The cell-motility factor Autotaxin (Autotaxin/lysoPLD or Enpp2) is an enzyme with both lysophospholipase D (lysoPLD) and nucleotide pyrophosphatase/phosphodiesterase activities and has recently been identified as a critical component of the major pathway for generation of the bioactive lipid mediator lysophosphatidic acid (LPA) in the blood. Transgenic FVB mice overexpressing Autotaxin/lysoPLD under the control of the alpha1-antitrypsin promoter (Enpp2-Tg mice) exhibited elevated plasma Autotaxin/lysoPLD protein, lysoPLD activity and LPA levels, with no detectable alteration in plasma levels of ATP, ADP, and adenosine. Ennp2-Tg mice displayed a pronounced bleeding diathesis characterized by markedly prolonged tail bleeding time (>10 min versus 3.2 ± 2.7 min in wild-type mice; p <0.001) and variable protection from thrombosis. Ennp2-Tg mice did not form occlusive thrombus in the carotid artery within 30 min following application of ferric chloride (versus a time to thrombotic occlusion of 9 ± 2 min in wild-type mice; p<0.001), and histologically, only mural thrombus was present along the ferric chloride-treated carotid arteries of the Ennp2-Tg mice. However, intravascular thrombosis in response to intravenous injection of collagen + epinephrine was normal in Ennp2-Tg mice. Enpp2-Tg mice exhibited normal platelet counts (928 ± 184 versus 808 ± 156 x 103/mm3), and normal platelet membrane protein expression, platelet aggregation, and coagulation parameters in ex vivo studies. Although LPA is a weak activator of platelets isolated from the majority of human donors, we found that treatment of isolated murine platelets with physiologically relevant levels of LPA (1μM) attenuated ADP (1μM)-induced and low-dose thrombin (0.01 – 0.05U/ml)-induced aggregation, but did not alter aggregation elicited by higher doses of thrombin or collagen. Treatment of murine platelets with LPA also elevated intraplatelet cAMP levels. Moreover, systemic administration of LPA to mice recapitulated the prolonged bleeding time observed in Enpp2-Tg mice. These results confirm the importance of Autotaxin/lysoPLD as the main determinant of circulating LPA levels and suggest a novel pathway for regulation of murine hemostasis and thrombosis involving the Autotaxin/lysoPLD-LPA axis.