Two pathways for lysophosphatidic acid production

Aoki, Junken; Inoue, Asuka; Okudaira, Shinichi

doi:10.1016/j.bbalip.2008.06.005

Cited by 387 publications

(351 citation statements)

References 90 publications

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“…Targeting downstream signaling molecules may result in more specific inhibition of LPA effects related to tumor metastasis, whereas upstream targets, such as LPA receptors, may be involved in a broader cellular effects, some of which should not be inhibited in normal physiology. Interestingly, PLA 2 s are not only involved in LPA signaling but also involved in LPA production (48). Thus, targeting these enzymes may present special advantages.…”

Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

Wang

Zhang

et al. 2009

Molecular Cancer Therapeutics

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We have already established human xenographic models for the effect of lysophosphatidic acid (LPA) on tumor metastasis in vivo. The purpose of this work is to establish a preclinical LPA effect model in immunocompetent mice. We first characterized the mouse epithelial ovarian cancer (EOC) cell line ID8 for its responsiveness to LPA in cell proliferation, migration, and invasion and compared these properties with those of human EOC. The signaling pathways related to cell migration were further investigated using pharmacologic and genetic approaches. The effects of LPA on the tumorigenesis of ID8 cells and mouse survival were then examined using two different mouse models (i.p. and orthotopic injections). LPA stimulated cell proliferation, migration, and invasion of mouse EOC ID8 cells in a manner closely resembling its activity in human EOC cells. The signaling pathways involved in LPAinduced cell migration in ID8 cells were also similar to those identified in human EOC cells. We have identified cyclooxygenase-1 and 15-lipoxygenase as two new signaling molecules involved in LPA-induced cell migration in both human and mouse EOC cells. In addition, LPA enhanced the tumorigenesis/metastasis of ID8 cell in vivo as assessed by increased tumor size, early onset of ascites formation, and reduced animal survival. We have established the first LPA-EOC preclinical model in immunocompetent mice. Because ID8 cells respond to LPA similar to human EOC cells, this model is very valuable in developing and testing therapeutic reagents targeting LPA in

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Section: Discussionmentioning

confidence: 99%

Lysophosphatidic acid stimulates cell migration, invasion, and colony formation as well as tumorigenesis/metastasis of mouse ovarian cancer in immunocompetent mice

Wang

Zhang

et al. 2009

Molecular Cancer Therapeutics

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“…LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.…”

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confidence: 99%

Novel Autotaxin Inhibitors for the Treatment of Osteoarthritis Pain: Lead Optimization via Structure-Based Drug Design

Jones

Pfeifer

Bleisch

et al. 2016

ACS Med. Chem. Lett.

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ABSTRACT:In an effort to develop a novel therapeutic agent aimed at addressing the unmet need of patients with osteoarthritis pain, we set out to develop an inhibitor for autotaxin with excellent potency and physical properties to allow for the clinical investigation of autotaxin-induced nociceptive and neuropathic pain. An initial hit identification campaign led to an aminopyrimidine series with an autotaxin IC 50 of 500 nM. X-ray crystallography enabled the optimization to a lead compound that demonstrated favorable potency (IC 50 = 2 nM), PK properties, and a robust PK/PD relationship. KEYWORDS: Autotaxin, tool molecule, osteoarthritis, LPA O steoarthritis (OA) is a highly prevalent disease affecting many adults including more than one out of three individuals aged 65 or older in the United States.1 In addition to significant accompanying pain, OA frequently leads to pronounced disability resulting in the loss of work, hospitalization, and joint replacement procedures.2 Current first-line pharmacological treatment options for OA focus on reducing inflammation and the associated pain. Nonsteroidal antiinflammatory drugs (NSAIDS) and selective COX-2 inhibitors are among the most prescribed medications for OA pain but unfortunately are also frequently accompanied by gastrointestinal, renal, and CV side effects, limiting their use. 3 Recently, the role of lyosophosphatidic acid (LPA) in certain inflammatory conditions has been studied. 4 LPA exists as a number of molecular species that have variable saturated and unsaturated fatty acid chains.5 Signaling of LPA through six GPCRs (LPA Receptors 1−6) has been shown to lead to the upregulation of inflammatory cytokines and matrix metalloproteinases, which contribute to the pathogenesis of OA. 6LPA signaling has also been associated with many other pathologies, such as pulmonary fibrosis and cancer. In vivo, the enzyme autotaxin (ATX), with lyosophosopholipase D activity, is the primary source of extracellular LPA, which results from the cleavage of choline from lysophosphatidylcholine (LPC) (Figure 1). LPA is also produced through action of secreted phospholipases A2 (sPLA2) on phosphatidic acid (PA), although this is believed to be a minor route of extracellular LPA production in vivo. 8,9 Autotaxin is an extracellular, 125 kDa protein that was originally characterized in 1993 by Stracke et al. as a motility stimulating protein. 10 In 2002, Umezu-Goto and co-workers demonstrated that ATX was the same protein as a known lysophopholipase D enzyme, which catalyzed the conversion of LPC to LPA.11 Autotaxin is a multidomain protein with two Nterminal somatomedin B-like domains, a centrally located phosphodiesterase domain, and a catalytically inactive nuclease-like domain on the C-terminal region. It is expressed in four main isoforms (ATXα−δ) with largely unknown differential functionality in vivo.7 The catalytic domain of ATX comprises two zinc ions coordinated with histidine and aspartic acid residues with a threonine alcohol serving as the nucleophile. A large hydro...

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“…The first pathway is hydrolysis of phosphatidic acid by phospholipase A1 and A2. It is believed that this pathway operates mainly in the cell or on the cell membrane where the phosphatidic acids are located (27). The second route is hydrolysis of lysophospholipids, such as lysophosphatidyl choline and isophosphatidyl serine by lysophospholipase ATX/D.…”

Section: Discussionmentioning

confidence: 99%