Identification of small-molecule inhibitors of autotaxin that inhibit melanoma cell migration and invasion

Saunders, Lauren P.; Ouellette, Amy; Bandle, Russ; Chang, William C.; Zhou, Hongwen; Misra, Raj N.; Cruz, Enrique M. De La; Braddock, Demetrios T.

doi:10.1158/1535-7163.mct-08-0463

Cited by 67 publications

(85 citation statements)

References 40 publications

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“…Further, additional analysis is needed to determine whether other pathway alterations may serve compensatory roles in the small set of patients with ENPP2 deletions. Together, these results indicate that the ATX/LPA signaling axis may be dysregulated in specifi c cancer subtypes, and that patients could potentially benefi t from targeted therapies blocking ATX/ LPA signaling Due to the pleiotropic connection of ATX in cancer pathology, considerable effort has been made to generate small molecule inhibitors that target its enzymatic activity ( 120,(164)(165)(166)(167)(168)(169)(170)(171)(172)(173). Using sensitive fl uorescence probes, such as TG-mTMP, Kawaguchi et al ( 174 ) identifi ed several novel ATX inhibitor scaffolds and solved the crystal structures of ATX-compound complexes at high resolution (1.75-1.95 Å).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 98%

“…Over the course of two decades of research, a large number of studies have established that in addition to cellautonomous cancer hallmarks such as differentiation ( 58,(103)(104)(105)(106), survival (107)(108)(109)(110)(111)(112), proliferation ( 58,(113)(114)(115)(116), and migration/metastatic behavior ( 50, 74,92,[117][118][119][120][121][122], the aberrant expression/amplifi cation of ATX activity can also dysregulate multiple cancer pathobiology systemic hallmarks including angiogenesis ( 119,123 ), metabolic homeostasis ( 56-59, 104, 124, 125 ), and immune system function ( 126 ).…”

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

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Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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a 125 kDa glycoprotein composed of 915 amino acids ( 1 ). Because it promoted chemotaxis on melanoma cells in an autocrine fashion, the protein was aptly named auto-taxin. Four years after the discovery of the fi rst variant, now commonly referred to as ATX ␣ , or melanoma ATX, a second isoform was cloned by the same team from the teratocarcinoma cell line, Ntera2D1. This polypeptide shared 94% identity with the melanoma protein and was immediately recognized as the alternatively spliced product of the same gene ( 2 ).The initial characterization of the fi rst isoform revealed that ATX biological activity was sensitive to pertussis toxin treatment. Furthermore, not only did the polypeptide share close homology with the murine pyrophosphatase/ type I phosphodiesterase (PDE) PC-1, including a threonine residue crucial for PDE enzymatic activity, but it was also able to hydrolyze PDE substrates in vitro ( 3 ). The confi rmation that ATX was an enzyme came when a new PDE, the PDE1/nucleotide pyrophosphatase (PD-1 ␣ /PDNP 2), was cloned from a cDNA library of human retina and found to be identical to the sequence of melanoma ATX ␣ with the exception of a missing stretch of 52 amino acids encoded by exon 12 in the central region of the open reading frame. The transcript of this variant, now frequently referred to as ATX ␤ , or teratoma ATX, produced a 863 amino acid polypeptide chain with a mass of 99,034 Da ( 4 ), and was independently isolated a few years later in mouse tissues ( 5 ). The third ATX isoform was detected for the fi rst time in rat brain, but was originally designated as PD-I ␣ , a brain-specifi c PDE I/nucleotide pyrophosphatase ( 6 ). Further research showed that PD-I ␣ was identical to ATX ␤ teratoma protein, except for the presence of an additional stretch of 25 amino acids encoded by an alternatively Abstract The ectonucleotide pyrophosphatase/phosphodiesterase type 2, more commonly known as autotaxin (ATX), is an ecto-lysophospholipase D encoded by the human ENNP2 gene. ATX is expressed in multiple tissues and participates in numerous key physiologic and pathologic processes, including neural development, obesity, infl ammation, and oncogenesis, through the generation of the bioactive lipid, lysophosphatidic acid. Overwhelming evidence indicates that altered ATX activity leads to oncogenesis and cancer progression through the modulation of multiple hallmarks of cancer pathobiology. Here, we review the structural and catalytic characteristics of the ectoenzyme, how its expression and maturation processes are regulated, and how the systemic integration of its pleomorphic effects on cells and tissues may contribute to cancer initiation, progression, and therapy. Additionally, the up-to-date spectrum of the most frequent ATX genomic alterations from The Cancer Genome Atlas project is reported for a subset of cancers. ( Fig. 1 ). In 1992, the fi rst alternatively spliced isoform was cloned from the melanoma cell line, A2058, and characterized as STRUCTURE AND ENZYMATIC ACTIVITY ATX belongs to the nuc...

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Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 98%

Section: Role In Physiology and Cancer Pathophysiologymentioning

confidence: 99%

Thematic Review Series: Phospholipases: Central Role in Lipid Signaling and Disease Autotaxin, a lysophospholipase D with pleomorphic effects in oncogenesis and cancer progression

Federico

Jeong

Vellano

et al. 2016

Journal of Lipid Research

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“…The TEV protease also contained a His tag, allowing a second Ni-NTA column to remove the TEV and His fragment. 18 …”

Section: Protein Expressionmentioning

confidence: 99%

“…Time courses of absorbance change were fitted to a linear function and the rate of cleavage was obtained using a p-nitrophenylate molar extinction coefficient of 18.5mM Ϫ1 cm Ϫ1 as described. 18 HPLC assay. The HPLC protocol used to measure Ap 3 A/Ap 4 A cleavage by NPP4 and for product identification is modified from that of Stocchi et al 22 The reactions containing varying concentrations of Ap 3 A/ Ap 4 A in the same buffer as in the absorbance change assay were started by addition of 0.2-1M NPP4 and quenched at various time points by an equal volume of 3M formic acid, or 0.5 N KOH and reacidified by glacial acetic acid to pH 6.…”

mentioning

confidence: 99%

NPP4 is a procoagulant enzyme on the surface of vascular endothelium

Albright

Chang

Robert

et al. 2012

Blood

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Ap3A is a platelet-dense granule component released into the extracellular space during the second wave of platelet aggregation on activation. Here, we identify an uncharacterized enzyme, nucleotide pyrophosphatase/phosphodiesterase-4 (NPP4), as a potent hydrolase of Ap3A capable of stimulating platelet aggregation and secretion. We demonstrate that NPP4 is present on the surface of vascular endothelium, where it hydrolyzes Ap3A into AMP and ADP, and Ap4A into AMP and ATP. Platelet aggregation assays with citrated platelet-rich plasma reveal that the primary and secondary waves of aggregation and dense granule release are strongly induced by nanomolar NPP4 in a concentration-dependent manner in the presence of Ap3A, while Ap3A alone initiates a primary wave of aggregation followed by rapid disaggregation. NPP2 and an active site NPP4 mutant, neither of which appreciably hydrolyzes Ap3A, have no effect on platelet aggregation and se- IntroductionThe formation of a platelet-rich thrombus stabilized by fibrin crosslinking is the final common pathway for arterial thrombosis, the most common disease process affecting adults in the United States. The first step in thrombus formation consists of platelet adhesion to the exposed subendothelial extracellular matrix at the site of vascular injury. Here, circulating blood platelets bind collagen via their GPVI receptors, and bind von Willebrand factor via GPIb, triggering inside-out activation of other surface integrins and the release of platelet granule contents into the extracellular space. 1 The release of preformed molecules stored in platelet-dense granules such as ADP, serotonin, and ionized calcium, then amplifies the clotting reaction beyond the platelet monolayer bound on the collagen surface to circulating platelets in the immediate vicinity of the damaged endothelium. This amplification is further augmented by the secretion of thromboxane A2. ADP binding to purinergic receptors on the platelet surface (P2Y1 and P2Y12) induces rapid calcium influx and mobilization resulting in platelet shape change, activation, and partial degranulation thus promoting platelet aggregation. On granule release, local ADP concentrations are estimated to exceed 500M, but ADP is quickly metabolized by ectoenzymes on the surface of endothelial cells (such as CD39 2,3 ) and soluble phosphohydrolyases in blood plasma which attenuate the prothrombotic response. [4][5][6][7] To sustain the clotting reaction, a slow and steady source of ADP at the site of the growing thrombus is required. Another preformed chemical released by platelet-dense granules at high concentrations, diadenosine triphosphate (Ap3A), has an ill-defined role in thrombus formation but has been suggested to provide a source of long-lasting ADP at the site of vascular injury.Ap3A is stored within platelet granules at high concentrations (ϳ20-30mM) and is released with ADP and ATP into the blood during thrombin-induced platelet aggregation at concentrations thought to range between 40 and 100M 8 (see supplemental Table ...

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“…Albeit the authors show that NSC48300 inhibited the growth of breast and brain tumors in murine models, the question of high interest remains that whether this activity is causally based on the inhibition of Taspase1 alone? Notably, besides its reported growth inhibition of numerous tumor cell lines, NSC48300 interfered with cell migration and invasion (4) and was patented as an antiangiogenic compound (5). This activity of the arsenic compound is further underlined by the results of the tail vein injection experiments, which might indicate potential limitations in the clinical use of NSC48300.…”

Section: To the Editormentioning

confidence: 99%