Cancer Metabolism

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

Abstract

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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Author information

F.C. conceived the study, designed and performed the experiments, interpreted the data and wrote the paper; L.D.L. performed activity assays and TCA cycle/ATP/oxygen measurements; G.L. and B.T. performed HPLC analysis; G.M. and F.D.G. performed fluorescence lifetime imaging of NADH; M.R.C. conceived and supervised the study, interpreted the data and revised the paper. All authors reviewed and approved the paper.

Correspondence to Maria Rosa Ciriolo.

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This work was supported by Italian Association for Cancer Research (AIRC, IG 15403). F.C. was supported by a fellowship from Italian Foundation for Cancer Research (FIRC-Bianca Marchino).

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Ciccarone, F., Di Leo, L., Lazzarino, G. et al. Aconitase 2 inhibits the proliferation of MCF-7 cells promoting mitochondrial oxidative metabolism and ROS/FoxO1-mediated autophagic response. Br J Cancer 122, 182–193 (2020). https://doi.org/10.1038/s41416-019-0641-0

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