Cell proliferation and drug sensitivity of human glioblastoma cells are altered by the stable modulation of cytosolic 5′-nucleotidase II

Cividini, Federico; Cros‐Perrial, Emeline; Pesi, Rossana; Machon, Christelle; Allegrini, Simone; Camici, Marcella; Dumontet, Charles; Jordheim, Lars Petter; Tozzi, Maria Grazia

doi:10.1016/j.biocel.2015.06.011

Cited by 19 publications

(22 citation statements)

References 36 publications

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“…This is to our knowledge the first published data on tumor growth of cells with modified cN-II expression. However, this is not consistent with the previously reported results showing no difference in in vitro proliferation on these same cell lines [ 19 ] or decreased in vitro cell growth in a neuroblastoma model [ 20 ]. Enhanced tumor growth in vivo is thus not simply explained by enhanced proliferation of the cell lines in short term in vitro cultures.…”

Section: Discussioncontrasting

confidence: 99%

“…First, transient inhibition by siRNA or by enzymatic inhibitors induce cell death in certain cancer cell models [ 12 , 17 ]. Second, modulation of cN-II expression was associated with variations in cell growth rate and intracellular energy charge [ 20 , 28 ]. Third, the highly conserved structure of cN-II among species, which is not limited to active and regulatory sites, suggested interactions with other cellular proteins [ 21 ].…”

Section: Discussionmentioning

confidence: 99%

“…Transient inhibition of its expression in neuroblastoma cells by siRNA indicated a role in cell survival as this was associated with induction of apoptosis [ 17 ], whereas a similar decrease in skeletal muscle cells induced activation of AMPK (which regulates lipid and glucose metabolism) as well as modified lipid metabolism and glucose transport [ 18 ]. In addition, stable up- or down-regulation of cN-II expression in various cancer cells has shown its implication in cell proliferation even though this is not the case for all cell lines [ 9 , 19 , 20 ]. Finally, the recently demonstrated interaction between cN-II and the inflammasome-protein NLRC4/Ipaf suggests other and still unknown properties of this enzyme in cell biology that could be independent of its enzymatic activity [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

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The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

et al. 2017

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The cytosolic 5’-nucleotidase cN-II is a highly conserved enzyme implicated in nucleotide metabolism. Based on recent observations suggesting additional roles not directly associated to its enzymatic activity, we studied human cancer cell models with basal or decreased cN-II expression. We developed cancer cells with stable inhibition of cN-II expression by transfection of shRNA-coding plasmids, and studied their biology. We show that human breast cancer cells MDA-MB-231 with decreased cN-II expression better adapt to the disappearance of glucose in growth medium under normoxic conditions than cells with a baseline expression level. This is associated with enhanced in vivo growth and a lower content of ROS in cells cultivated in absence of glucose due to more efficient mechanisms of elimination of ROS. Conversely, cells with low cN-II expression are more sensitive to glucose deprivation in hypoxic conditions. Overall, our results show that cN-II regulates the cellular response to glucose deprivation through a mechanism related to ROS metabolism and defence.

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Section: Discussioncontrasting

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

et al. 2017

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“…As a consequence, a number of cell models in which cN-II was, at some degree, silenced were developed, to unravel the molecular consequences of the enzyme inhibition. In a human astrocytoma cell line (ADF), transitory and partial cN-II silencing prompted apoptosis [ 13 ], while partial constitutive cN-II knockdown caused a decrease of cell proliferation [ 14 ]. On the other hand, the hyperexpression of cN-II in ADF cells was accompanied by an increase in cell proliferation [ 14 ].…”

Section: Introductionmentioning

confidence: 99%

“…In a human astrocytoma cell line (ADF), transitory and partial cN-II silencing prompted apoptosis [ 13 ], while partial constitutive cN-II knockdown caused a decrease of cell proliferation [ 14 ]. On the other hand, the hyperexpression of cN-II in ADF cells was accompanied by an increase in cell proliferation [ 14 ]. Bovine cN-II has been heterologously expressed in Saccharomyces cerevisiae [ 15 ] which possesses a soluble 5′-nucleotidase, coded by gene ISN1 [ 16 ].…”

Section: Introductionmentioning

confidence: 99%

Cytosolic 5′-Nucleotidase II Silencing in a Human Lung Carcinoma Cell Line Opposes Cancer Phenotype with a Concomitant Increase in p53 Phosphorylation

Pesi

Petrotto

Colombaioni

et al. 2018

IJMS

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Purine homeostasis is maintained by a purine cycle in which the regulated member is a cytosolic 5′-nucleotidase II (cN-II) hydrolyzing IMP and GMP. Its expression is particularly high in proliferating cells, indeed high cN-II activity or expression in hematological malignancy has been associated to poor prognosis and chemoresistance. Therefore, a strong interest has grown in developing cN-II inhibitors, as potential drugs alone or in combination with other compounds. As a model to study the effect of cN-II inhibition we utilized a lung carcinoma cell line (A549) in which the enzyme was partially silenced and its low activity conformation was stabilized through incubation with 2-deoxyglucose. We measured nucleotide content, reduced glutathione, activities of enzymes involved in glycolysis and Krebs cycle, protein synthesis, mitochondrial function, cellular proliferation, migration and viability. Our results demonstrate that high cN-II expression is associated with a glycolytic, highly proliferating phenotype, while silencing causes a reduction of proliferation, protein synthesis and migration ability, and an increase of oxidative performances. Similar results were obtained in a human astrocytoma cell line. Moreover, we demonstrate that cN-II silencing is concomitant with p53 phosphorylation, suggesting a possible involvement of this pathway in mediating some of cN-II roles in cancer cell biology.

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The druggability of intracellular nucleotide-degrading enzymes

Rampazzo

Tozzi

Dumontet

et al. 2015

Cancer Chemother Pharmacol

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Nucleotide metabolism is the target of a large number of anticancer drugs including antimetabolites and specific enzyme inhibitors. We review scientific findings that over the last 10-15 years have allowed the identification of several intracellular nucleotide-degrading enzymes as cancer drug targets, and discuss further potential therapeutic applications for Rcl, SAMHD1, MTH1 and cN-II. We believe that enzymes involved in nucleotide metabolism represent potent alternatives to conventional cancer chemotherapy targets.

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Cell proliferation and drug sensitivity of human glioblastoma cells are altered by the stable modulation of cytosolic 5′-nucleotidase II

Cited by 19 publications

References 36 publications

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

The cytosolic 5′-nucleotidase cN-II lowers the adaptability to glucose deprivation in human breast cancer cells

Cytosolic 5′-Nucleotidase II Silencing in a Human Lung Carcinoma Cell Line Opposes Cancer Phenotype with a Concomitant Increase in p53 Phosphorylation

The druggability of intracellular nucleotide-degrading enzymes

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