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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...
Autores principales: | , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group UK
2019
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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. |
format | Online Article Text |
id | pubmed-7051954 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2019 |
publisher | Nature Publishing Group UK |
record_format | MEDLINE/PubMed |
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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