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Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response

BACKGROUND: Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement...

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Autores principales: Ciccarone, Fabio, Di Leo, Luca, Lazzarino, Giacomo, Maulucci, Giuseppe, Di Giacinto, Flavio, Tavazzi, Barbara, Ciriolo, Maria Rosa
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051954/
https://www.ncbi.nlm.nih.gov/pubmed/31819175
http://dx.doi.org/10.1038/s41416-019-0641-0
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author Ciccarone, Fabio
Di Leo, Luca
Lazzarino, Giacomo
Maulucci, Giuseppe
Di Giacinto, Flavio
Tavazzi, Barbara
Ciriolo, Maria Rosa
author_facet Ciccarone, Fabio
Di Leo, Luca
Lazzarino, Giacomo
Maulucci, Giuseppe
Di Giacinto, Flavio
Tavazzi, Barbara
Ciriolo, Maria Rosa
author_sort Ciccarone, Fabio
collection PubMed
description BACKGROUND: Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far. METHODS: Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics. RESULTS: We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst. CONCLUSIONS: This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies.
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spelling pubmed-70519542020-12-10 Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response Ciccarone, Fabio Di Leo, Luca Lazzarino, Giacomo Maulucci, Giuseppe Di Giacinto, Flavio Tavazzi, Barbara Ciriolo, Maria Rosa Br J Cancer Article BACKGROUND: Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. Aconitase 2 (ACO2) participates in the TCA cycle by converting citrate to isocitrate, but no evident demonstrations of its involvement in cancer metabolism have been provided so far. METHODS: Biochemical assays coupled with molecular biology, in silico, and cellular tools were applied to circumstantiate the impact of ACO2 in the breast cancer cell line MCF-7 metabolism. Fluorescence lifetime imaging microscopy (FLIM) of NADH was used to corroborate the changes in bioenergetics. RESULTS: We showed that ACO2 levels are decreased in breast cancer cell lines and human tumour biopsies. We generated ACO2- overexpressing MCF-7 cells and employed comparative analyses to identify metabolic adaptations. We found that increased ACO2 expression impairs cell proliferation and commits cells to redirect pyruvate to mitochondria, which weakens Warburg-like bioenergetic features. We also demonstrated that the enhancement of oxidative metabolism was supported by mitochondrial biogenesis and FoxO1-mediated autophagy/mitophagy that sustains the increased ROS burst. CONCLUSIONS: This work identifies ACO2 as a relevant gene in cancer metabolic rewiring of MCF-7 cells, promoting a different utilisation of pyruvate and revealing the potential metabolic vulnerability of ACO2-associated malignancies. Nature Publishing Group UK 2019-12-10 2020-01-21 /pmc/articles/PMC7051954/ /pubmed/31819175 http://dx.doi.org/10.1038/s41416-019-0641-0 Text en © The Author(s), under exclusive licence to Cancer Research UK 2019 https://creativecommons.org/licenses/by/4.0/Note This work is published under the standard license to publish agreement. After 12 months the work will become freely available and the license terms will switch to a Creative Commons Attribution 4.0 International (CC BY 4.0).
spellingShingle Article
Ciccarone, Fabio
Di Leo, Luca
Lazzarino, Giacomo
Maulucci, Giuseppe
Di Giacinto, Flavio
Tavazzi, Barbara
Ciriolo, Maria Rosa
Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title_full Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title_fullStr Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title_full_unstemmed Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title_short Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response
title_sort aconitase 2 inhibits the proliferation of mcf-7 cells promoting mitochondrial oxidative metabolism and ros/foxo1-mediated autophagic response
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7051954/
https://www.ncbi.nlm.nih.gov/pubmed/31819175
http://dx.doi.org/10.1038/s41416-019-0641-0
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