An Ecto‐Nucleotide Pyrophosphatase Is One of the Main Enzymes Involved in the Extracellular Metabolism of ATP in Rat C6 Glioma

Grobben, Bert; Anciaux, Katelijne; Roymans, Dirk; Stefan, Cristiana; Bollen, Mathieu; Esmans, Eddy L.; Slegers, Herman

doi:10.1046/j.1471-4159.1999.0720826.x

Cited by 97 publications

(100 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…49 Notably, a surface-located nucleotide pyrophosphatase (most likely E-NPP1) had been identified as the major enzyme responsible for the metabolism of extracellular ATP in glioma. 50 As suggested by Aerts and colleagues, highly proliferating cells require an excess of purine and pyrimidine nucleotides, hence the overexpression of ENPP1 in glioblastoma tumours is likely due to its function in nucleotide recycling. 17 Our expression data strongly support this hypothesis and further links it to stem cells in glioblastoma.…”

Section: Discussionmentioning

confidence: 97%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

View full text Add to dashboard Cite

Glioblastomas are highly aggressive brain tumours and are characterised by substantial cellular heterogeneity within a single tumour. A sub-population of glioblastoma stem-like cells (GSCs) that shares properties with neural precursor cells has been described, exhibiting resistance to therapy and therefore being considered responsible for the high recurrence rate in glioblastoma. To elucidate the underlying cellular processes we investigated the role of phosphatases in the GSC phenotype, using an in vitro phosphatome-wide RNA interference screen. We identified a set of genes, the knockdown of which induces a significant decrease in the glioma stem cell marker CD133, indicating a role in the glioblastoma stem-like phenotype. Among these genes, the ecto-nucleotidase ENPP1 (ectonucleotide pyrophosphatase/phosphodiesterase 1) was found to be highly expressed in GSCs compared with normal brain and neural stem cells. Knockdown of ENPP1 in cultured GSCs resulted in an overall downregulation of stem cell-associated genes, induction of differentiation into astrocytic cell lineage, impairment of sphere formation, in addition to increased cell death, accumulation of cells in G1/G0 cell cycle phase and sensitisation to chemotherapeutic treatment. Genome-wide gene expression analysis and nucleoside and nucleotide profiling revealed that knockdown of ENPP1 affects purine and pyrimidine metabolism, suggesting a link between ENPP1 expression and a balanced nucleoside-nucleotide pool in GSCs. The phenotypic changes in E-NPP1-deficient GSCs are assumed to be a consequence of decreased transcriptional function of E2F1. Together, these results reveal that E-NPP1, by acting upstream of E2F1, is indispensable for the maintenance of GSCs in vitro and hence required to keep GSCs in an undifferentiated, proliferative state. Glioblastoma, classified by the WHO (World Health Organization) as grade IV astrocytoma, 1 is the most common primary malignant brain tumour in adults. Despite progress in surgical resection, radiation and chemotherapy, glioblastoma remains a deadly disease with a median survival time of about 1 year. 2 One particular therapeutic challenge for glioblastoma treatment is posed by their remarkable intratumoural cellular heterogeneity. Several studies indicate the existence of a highly tumourigenic, sub-population of cancer cells with stemlike characteristics. [3][4][5] There is substantial evidence that these so-called cancer stem cells have inherent chemotherapy and radiation resistance. 6,7 These findings suggest that cancer cells harbouring stem cell-like characteristics are responsible for ineffective therapy, explaining high recurrence rates despite significant reduction in tumour volume. Glioblastoma stem-like cells (GSCs) share properties with neural precursor cells, such as a capacity for self-renewal, differentiation and maintained proliferation, as well as stem cell marker expression. 4,5,8,9 GSCs were originally defined by expression of CD133 (Prominin-1) and its extracellular AC133 epitope. 4 Although recent...

show abstract

Section: Discussionmentioning

confidence: 97%

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

et al. 2014

View full text Add to dashboard Cite

show abstract

“…Reported K m values of E-NPPs for ATP range between 17 and 300 μM [354,360,365,369]. For a nucleotide pyrophosphatase isolated from rat liver, K m values for UDP-glucose and NAD + were found to be similar to those for ATP and UTP [360].…”

Section: General Properties and Functional Rolementioning

confidence: 95%

“…NPP1: Endogenous enzyme expressed by rat C6 glioma cells, presumably NPP1, application of 10 μM [γ-32 P]ATP. The pattern of product formation varies, however, with the initial concentration of ATP [369]. The formation of P i could in part have resulted from the presence of additional ectonucleotidases.…”

Section: General Molecular Propertiesmentioning

confidence: 99%

“…One of the limitations results from the fact that classical inhibitors of P2 receptors can also inhibit E-NPPs [351,369]. In principle, E-NPPs could modulate nucleotide signaling by hydrolyzing purinoceptors agonists and together with APs or ecto-5′-nucleotidase produce adenosine.…”

Section: Downstream Signaling Purinergic Mechanismsmentioning

confidence: 99%

“…In principle, E-NPPs could modulate nucleotide signaling by hydrolyzing purinoceptors agonists and together with APs or ecto-5′-nucleotidase produce adenosine. C6 glioma cells express a surface-located nucleotide pyrophosphatase (presumably NPP1) as the major ecto-nucleotidase [369] that can modulate purinergic receptor function. Furthermore, inhibition of NPPase activity in C6 glioma cells was found to potentiate the inhibitory effect of ATP and ADP on the isoproterenol-induced increase in intracellular cyclic AMP synthesis, corroborating a role of NPPs in modulating purinoceptor-mediated signal transduction [435].…”

Section: Downstream Signaling Purinergic Mechanismsmentioning

confidence: 99%

See 2 more Smart Citations

Cellular function and molecular structure of ecto-nucleotidases

Zimmermann

Zebisch

Sträter

2012

Purinergic Signalling

888

922

View full text Add to dashboard Cite

Ecto-nucleotidases play a pivotal role in purinergic signal transmission. They hydrolyze extracellular nucleotides and thus can control their availability at purinergic P2 receptors. They generate extracellular nucleosides for cellular reuptake and salvage via nucleoside transporters of the plasma membrane. The extracellular adenosine formed acts as an agonist of purinergic P1 receptors. They also can produce and hydrolyze extracellular inorganic pyrophosphate that is of major relevance in the control of bone mineralization. This review discusses and compares four major groups of ectonucleotidases: the ecto-nucleoside triphosphate diphosphohydrolases, ecto-5′-nucleotidase, ecto-nucleotide pyrophosphatase/phosphodiesterases, and alkaline phosphatases. Only recently and based on crystal structures, detailed information regarding the spatial structures and catalytic mechanisms has become available for members of these four ecto-nucleotidase families. This permits detailed predictions of their catalytic mechanisms and a comparison between the individual enzyme groups. The review focuses on the principal biochemical, cell biological, catalytic, and structural properties of the enzymes and provides brief reference to tissue distribution, and physiological and pathophysiological functions.

show abstract

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

Picher¹,

Graff²,

Lee³

2003

Arthritis & Rheumatism

View full text Add to dashboard Cite

show abstract

An Ecto‐Nucleotide Pyrophosphatase Is One of the Main Enzymes Involved in the Extracellular Metabolism of ATP in Rat C6 Glioma

Cited by 97 publications

References 34 publications

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Stem cell characteristics in glioblastoma are maintained by the ecto-nucleotidase E-NPP1

Cellular function and molecular structure of ecto-nucleotidases

Extracellular nucleotide metabolism and signaling in the pathophysiology of articular cartilage

Contact Info

Product

Resources

About