Abstract
BackgroundDeregulation 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.MethodsBiochemical 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.ResultsWe 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.ConclusionsThis 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.
Highlights
Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth
We have focused the attention on Aconitase 2 (ACO2) because it belongs to a branch of the TCA cycle important for cancer metabolic features as it is interposed between citrate, which plays a role in lipid anabolism, and α-KG that can be replenished by glutamine anaplerosis.[1,2]
ACO2 expression is reduced in breast cancer and increasing its levels dampens cell proliferation of MCF-7 cells To assess the expression of ACO2 in breast cancer cells, we compared the non-tumorigenic human breast epithelial cell line MCF10A with a panel of breast cancer cell lines, most of which exhibit a dramatic reduction of ACO2 protein levels (Fig. 1a)
Summary
Deregulation of the tricarboxylic acid cycle (TCA) due to mutations in specific enzymes or defective aerobic metabolism is associated with tumour growth. The TCA cycle represents the core pathway for aerobic oxidation of carbohydrates, lipids and proteins in mitochondria, by supplying the reduced coenzymes NADH and FADH2 necessary for ATP production through the oxidative phosphorylation (OXPHOS).[1,2] many cancer cells prefer to enhance the glycolytic rate for energetic purposes, by favouring glucose transporters and glycolytic enzymes rather than the TCA cycle machinery, and this results in increased lactate production even in normoxia, a phenomenon known as aerobic glycolysis or the ‘Warburg effect’.3 This peculiarity is significant as the intermediates of the TCA cycle can diverge towards anabolic reactions, leading to amino acids, lipids and nucleotide synthesis necessary for supporting the high rate of proliferation.[1,2] Based on this, the manipulation of glycolysis and of the TCA cycle reactions by cancer cells represents a core strategy for their metabolic demands, such as energy production, biomass assimilation and redox control. Received: 28 June 2019 Revised: 3 October 2019 Accepted: 28 October 2019 Published online: 10 December 2019
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