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Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway

Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentr...

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Autores principales: Pesi, Rossana, Allegrini, Simone, Garcia-Gil, Mercedes, Piazza, Lucia, Moschini, Roberta, Jordheim, Lars Petter, Camici, Marcella, Tozzi, Maria Grazia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268954/
https://www.ncbi.nlm.nih.gov/pubmed/34209768
http://dx.doi.org/10.3390/ijms22137004
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author Pesi, Rossana
Allegrini, Simone
Garcia-Gil, Mercedes
Piazza, Lucia
Moschini, Roberta
Jordheim, Lars Petter
Camici, Marcella
Tozzi, Maria Grazia
author_facet Pesi, Rossana
Allegrini, Simone
Garcia-Gil, Mercedes
Piazza, Lucia
Moschini, Roberta
Jordheim, Lars Petter
Camici, Marcella
Tozzi, Maria Grazia
author_sort Pesi, Rossana
collection PubMed
description Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors.
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spelling pubmed-82689542021-07-10 Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway Pesi, Rossana Allegrini, Simone Garcia-Gil, Mercedes Piazza, Lucia Moschini, Roberta Jordheim, Lars Petter Camici, Marcella Tozzi, Maria Grazia Int J Mol Sci Article Cytosolic 5′-nucleotidase II (cN-II) is an allosteric catabolic enzyme that hydrolyzes IMP, GMP, and AMP. The enzyme can assume at least two different structures, being the more active conformation stabilized by ATP and the less active by inorganic phosphate. Therefore, the variation in ATP concentration can control both structure and activity of cN-II. In this paper, using a capillary electrophoresis technique, we demonstrated that a partial silencing of cN-II in a pulmonary carcinoma cell line (NCI-H292) is accompanied by a decrease in adenylate pool, without affecting the energy charge. We also found that cN-II silencing decreased proliferation and increased oxidative metabolism, as indicated by the decreased production of lactate. These effects, as demonstrated by Western blotting, appear to be mediated by both p53 and AMP-activated protein kinase, as most of them are prevented by pifithrin-α, a known p53 inhibitor. These results are in line with our previous observations of a shift towards a more oxidative and less proliferative phenotype of tumoral cells with a low expression of cN-II, thus supporting the search for specific inhibitors of this enzyme as a therapeutic tool for the treatment of tumors. MDPI 2021-06-29 /pmc/articles/PMC8268954/ /pubmed/34209768 http://dx.doi.org/10.3390/ijms22137004 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Pesi, Rossana
Allegrini, Simone
Garcia-Gil, Mercedes
Piazza, Lucia
Moschini, Roberta
Jordheim, Lars Petter
Camici, Marcella
Tozzi, Maria Grazia
Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title_full Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title_fullStr Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title_full_unstemmed Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title_short Cytosolic 5′-Nucleotidase II Silencing in Lung Tumor Cells Regulates Metabolism through Activation of the p53/AMPK Signaling Pathway
title_sort cytosolic 5′-nucleotidase ii silencing in lung tumor cells regulates metabolism through activation of the p53/ampk signaling pathway
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8268954/
https://www.ncbi.nlm.nih.gov/pubmed/34209768
http://dx.doi.org/10.3390/ijms22137004
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