Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:3.1.1.5 (neuropathy target esterase)
 1,070 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Alkyl-lysophospholipids inhibit the growth of Meth A sarcoma cells in vitro. In contrast, murine bone marrow macrophages are not sensitive to the destructive effect of these substances. Since alkyl-lysophospholipids are antimetabolites in the synthesis of 3-sn-phosphatidylcholine, tumor cell destruction can be correlated with the disturbance of this metabolism. A decreased synthesis of 3-sn-phosphatidylcholine is accompanied by an increased degradation of cellular 3-sn-phosphatidylcholine in the presence of alkyl-lysophospholipids. As a consequence, endogeneously formed lysophospholipid accumulates, although the lysophospholipase is found to be stimulated. This accumulation of endogeneous lysophospholipids might be due to the fact that a high percentage of these compounds contain an alkyl bond which cannot be split by a lysophospholipase. On the other hand, the reacylation of the formed lysophospholipids is partially blocked as the lysophosphatidylcholine acyltransferase is inhibited by the added alkyllysophospholipids. An accumulation of potentially cytotoxic lysophospholipids in tumor cells might be an additional factor in the tumor cell destruction by alkyl-lysophospholipids.
Cancer Res 1979 Nov
PMID:Disturbance of phospholipid metabolism during the selective destruction of tumor cells induced by alkyl-lysophospholipids. 49 95

Eosinophils derived from HL-60 cells share many of the abnormalities of granule histochemistry and morphology frequently seen in eosinophils of patients with certain malignancies, especially those seen in acute myelomonocytic leukemia with abnormal eosinophils (FAB class M4eo). In order to understand the pathogenesis of these abnormalities, four enzymes, characteristic of the eosinophil, were studied in HL-60 promyelocytic leukemia cells at various stages of eosinophilic differentiation. Using biochemical and ultrahistochemical techniques, the following differences from normal eosinophil development were demonstrated. First, both myeloperoxidase and eosinophil peroxidase coexisted in the population of maturing HL-60 eosinophils. Second, the granules formed from the condensation of material in vacuoles which were derived from dilated segments of the endoplasmic reticulum; the role of the Golgi apparatus in processing of peroxidase appeared minimal. Third, low levels of lysophospholipase and arylsulfatase were present in the cells compared to normal eosinophils. Finally, crystallizations resembling precursor structures of Auer rods appeared in the granules of about 5% of the cells. These findings suggest that several disorders of the control of protein synthesis and processing exist in HL-60 eosinophils which may be responsible for the abnormal granule morphology and histochemistry.
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PMID:Synthesis of eosinophil-associated enzymes in HL-60 promyelocytic leukemia cells. 301 41

Serum stimulates both Ca2+ mobilization and colony growth of many small cell lung cancer (SCLC) cell lines, but the factors involved remain unknown. We demonstrate that 1-oleoyl-lysophosphatidic acid (LPA), like serum, induced a dose-dependent increase in intracellular Ca2+ in the H-510, H-345, and H-69 SCLC cell lines with half maximal concentrations of 18 nM, 22 nM, and 20 nM, respectively. Two lines of evidence revealed that LPA was the major factor in serum responsible for mobilizing Ca2+ in these SCLC cell lines: (a) both LPA and serum exhibited cross desensitization in the Ca2+ mobilization assay; and (b) phospholipase B pretreatment of either LPA or serum prevented the ability of these agents to stimulate Ca2+ mobilization. In marked contrast, LPA at concentrations between 2 nM and 20 microM, unlike serum, failed to stimulate colony formation. Furthermore, phospholipase B treatment of serum did not inhibit serum-induced colony formation. We therefore searched for growth factors which could induce colony growth through a Ca(2+)-independent pathway. We found that both human recombinant hepatocyte growth factor and stem cell growth factor increased colony growth, but failed to stimulate an increase in intracellular Ca2+ in the H-510, H-345, and H-69 SCLC cell lines. Our results indicate that LPA-depleted serum, hepatocyte growth factor, and stem cell growth factor stimulate colony formation in SCLC cells through a Ca(2+)-independent pathway.
Cancer Res 1994 Dec 01
PMID:Lysophosphatidic acid-depleted serum, hepatocyte growth factor and stem cell growth factor stimulate colony growth of small cell lung cancer cells through a calcium-independent pathway. 752 56

Clofazimine, a riminophenazine antimicrobial agent, and its analogue B669 were investigated for their effects on FaDu cells, a human squamous carcinoma cell line. These agents, at concentrations within the therapeutic range (0.25-2 micrograms/ml), caused a dose-dependent tumor cell cytotoxicosis which was greatly enhanced in the presence of human neutrophils. The neutrophil-mediated increment in tumoricidal activity, but not the direct antitumor effects of the drugs per se, was inhibited by catalase. The effects of these drugs on three more cell carcinoma lines as well as on two primary cultures and a noncarcinoma cell line were also investigated and compared with the activity of the standard antitumor chemotherapeutic agents bleomycin, cisplatin, and methotrexate. All seven cultures were sensitive to clofazimine and B669 compared to six that were sensitive to cisplatin, three that were sensitive to bleomycin, and one that was sensitive to methotrexate. The treatment of FaDu cells with clofazimine and B669 was associated with enhanced activity of phospholipase A2, as evidenced by increased release of radiolabeled arachidonate and lysophosphatidylcholine from membrane phospholipids. Inhibitors of arachidonic acid metabolism, protein kinase C inhibitors, as well as water and lipid soluble antioxidants failed to protect the cells against the cytotoxic activity of clofazimine and B669. However, alpha-tocopherol, a lysophospholipid-complexing agent, completely blocked the antiproliferative effects of the riminophenazines and also protected the cells against the direct cytotoxic effect of lysophosphatidylcholine, while the lysophospholipid-neutralizing enzyme lysophospholipase protected against the riminophenazines. These observations demonstrate that the tumoricidal properties of clofazimine and B669 are probably due to increases in the lysophospholipid content of cell membranes.
Cancer Res 1993 Jan 15
PMID:The riminophenazine agents clofazimine and B669 inhibit the proliferation of cancer cell lines in vitro by phospholipase A2-mediated oxidative and nonoxidative mechanisms. 767 73

Phosphatidylserine-specific phospholipase A1 (PS-PLA1), which acts specifically on phosphatidylserine (PS) and 1-acyl-2-lysophosphatidylserine (lyso-PS) to hydrolyze fatty acids at the sn-1 position of these phospholipids, was first identified in rat platelets (Sato, T., Aoki, J., Nagai, Y., Dohmae, N., Takio, K., Doi, T., Arai, H., and Inoue, K. (1997) J. Biol. Chem. 272, 2192-2198). In this study we isolated and sequenced cDNA clones encoding human PS-PLA1, which showed 80% homology with rat PS-PLA1 at the amino acid level. In addition to an mRNA encoding a 456-amino acid product (PS-PLA1), an mRNA with four extra bases inserted at the boundary of the exon-intron junction was detected in human tissues and various human cell lines. This mRNA is most probably produced via an alternative use of the 5'-splicing site (two consensus sequences for RNA splicing occur at the boundary of the exon-intron junction) and encodes a 376-amino acid product (PS-PLA1DeltaC) that lacks two-thirds of the C-terminal domain of PS-PLA1. Unlike PS-PLA1, PS-PLA1DeltaC hydrolyzed exclusively lyso-PS but not PS appreciably. Any other phospholipids such as phosphatidylcholine (PC), phosphatidylethanolamine (PE), phosphatidic acid (PA), and their lyso derivatives were not hydrolyzed at all. These data demonstrated that PS-PLA1DeltaC exhibits lyso-PS-specific lysophospholipase activity and that the C-terminal domain of PS-PLA1 is responsible for recognizing diacylphospholipids. In addition, human PS-PLA1 gene was mapped to chromosome 3q13.13-13.2 and was unexpectedly identical to the nmd gene, which is highly expressed in nonmetastatic melanoma cell lines but poorly expressed in metastatic cell lines (van Groningen, J. J., Bloemers, H. P., and Swart, G. W. (1995) Cancer Res. 55, 6237-6243).
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PMID:An alternative splicing form of phosphatidylserine-specific phospholipase A1 that exhibits lysophosphatidylserine-specific lysophospholipase activity in humans. 1019 88

Analytical methods optimized for micellar F5cys-MP-PEG(2000)-DPSE protein-lipopolymer conjugate are presented. The apparent micelle molecular weight, determined by size exclusion chromatography, ranged from 330 to 960 kDa. The F5cys antibody and conjugate melting points, determined by differential scanning calorimetry, were near 82 degrees C. Traditional methods for characterizing monodisperse protein species were inapplicable to conjugate analysis. The isoelectric point of F5cys (9.2) and the conjugate (8.9) were determined by capillary isoelectric focusing (cIEF) after addition of the zwitterionic detergent CHAPS to the buffer. Conjugate incubation with phospholipase B selectively removed DSPE lipid groups and dispersed the conjugate prior to separation by chromatographic methods. Alternatively, adding 2-propanol (29.4 vol %) and n-butanol (4.5 vol %) to buffers for salt-gradient cation exchange chromatography provided gentler, nonenzymatic dispersion, resulting in well-resolved peaks. This method was used to assess stability, identify contaminants, establish lot-to-lot comparability, and determine the average chromatographic purity (93%) for conjugate lots, described previously. The F5cys amino acid content was confirmed after conjugation. The expected conjugate avidity for immobilized HER-2/neu was measured by bimolecular interaction analysis (BIAcore). Mock therapeutic assemblies were made by conjugate insertion into preformed doxorubicin-encapsulating liposomes for antibody-directed uptake of doxorubicin by HER2-overexpressing cancer cells in vitro. Together these developed assays established that the manufacturing method as described in the first part of this study consistently produced F5cys-MP-PEG(2000)-DSPE having sufficient purity, stability, and functionality for use in preclinical toxicology investigations.
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PMID:Preclinical manufacture of anti-HER2 liposome-inserting, scFv-PEG-lipid conjugate. 2. Conjugate micelle identity, purity, stability, and potency analysis. 1590 61

Autotaxin (NPP2) is an extracellular protein that is upregulated in various malignancies, including breast and lung cancer. It potently stimulates cell proliferation, cell motility and angiogenesis, which is accounted for by its intrinsic lysophospholipase-D activity that generates the lipid mediators lysophosphatidic acid and sphingosine-1-phosphate. Based on its structural similarities with the better characterized nucleotide pyrophosphatase/phosphodiesterase NPP1, it has always been assumed that NPP2 is also synthesized as a type-II integral membrane protein and that extracellular NPP2 is generated from this membrane precursor. We show here, however, using domain swapping and mutagenesis experiments as well as N-terminal protein sequencing, that NPP2 is actually synthesized as a pre-pro-enzyme and that the proteolytically processed protein is secreted. Following the removal of a 27-residue signal peptide by the signal peptidase, NPP2 is subsequently cleaved by proprotein convertases (PCs). The removal of an N-terminal octapeptide by PCs is associated with an enhanced activity of NPP2 as a lysophospholipase D. These novel insights in the maturation of NPP2 have also implications for the development of NPP2 inhibitors as potential anti-cancer agents.
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PMID:Proteolytic maturation and activation of autotaxin (NPP2), a secreted metastasis-enhancing lysophospholipase D. 1598 67

Autotaxin or NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2) is a secreted lysophospholipase-D that promotes metastasis and tumor growth by its ability to generate lysophosphatidic acid. Considerable evidence suggests that inhibitors of NPP2 can be used as a novel therapy for the treatment of cancer. Although most attention is currently directed toward the development of inhibitors of the catalytic site, we have explored whether NPP2 can also be targeted through its non-catalytic nuclease-like domain. We demonstrate here that the catalytic and nuclease-like domains are covalently linked by an essential disulfide bridge between Cys(413) and Cys(805). Within the nuclease-like domain, residues 829-850 are involved in the secretion of NPP2, and Lys(852) is required for the expression of catalytic activity. These data show that the nuclease-like domain is crucial for catalysis by NPP2 and is a possible target to generate inhibitors.
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PMID:Domain interplay mediated by an essential disulfide linkage is critical for the activity and secretion of the metastasis-promoting enzyme autotaxin. 1932 27

Autotaxin, also known as NPP2 (nucleotide pyrophosphatase/phosphodiesterase 2), is a secreted lysophospholipase-D that generates lysophosphatidic acid and thereby promotes the metastatic and invasive properties of tumor cell as well as angiogenesis. We show here that, in mice, NPP2 is cleared from the circulation within minutes and is retained by the liver sinusoidal endothelial cells (LSECs). The binding of NPP2 to isolated LSECs resulted in its degradation and could be competed for with ligands of the scavenger receptor family. Our finding that circulating NPP2 has a rapid turnover has important implications for its development as an anti-cancer target.
Cancer Lett 2009 Nov 01
PMID:Rapid clearance of the circulating metastatic factor autotaxin by the scavenger receptors of liver sinusoidal endothelial cells. 1948 19

The ability of cancer cells to invade and metastasize is the major cause of death in cancer patients. Autotaxin (ATX) is a secreted lysophospholipase whose level of expression within tumors correlates strongly with their aggressiveness and invasiveness. ATX is the major enzyme involved in the production of lysophosphatidic acid (LPA), a phospholipid that is known to act mostly through its three first characterized receptors (LPA(1), LPA(2), and LPA(3)). Tumor cell invasion across tissue boundaries and metastasis are dependent on the capacity of invasive cancer cells to breach the basement membrane. This process can be initiated by the formation of the actin-rich cell protrusions, invadopodia. In this study, we show that ATX is implicated in the formation of invadopodia in various cancer cells types and this effect is dependent on the production of LPA. We further provide evidence that LPA(4) signaling in fibrosarcoma cells regulates invadopodia formation downstream of ATX, a process mediated through the activation of EPAC by cyclic AMP and subsequent Rac1 activation. Results using LPA(4) shRNA support the requirement of the LPA(4) receptor for cell invasion and in vivo metastasis formation. This work presents evidence that blocking the LPA receptor, LPA(4), in fibrosarcoma cells could provide an additional tool to improve the efficacy of treatment of metastasis in patients. Because LPA receptors and ATX are currently being targeted in preclinical trials, the current findings should stimulate future studies to evaluate the expression pattern and clinical outcome of LPA(4), together with other LPA receptors, in various cancer patients.
Cancer Res 2010 Jun 01
PMID:Autotaxin promotes cancer invasion via the lysophosphatidic acid receptor 4: participation of the cyclic AMP/EPAC/Rac1 signaling pathway in invadopodia formation. 2048 39


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