Aspirin disrupts acetyl-CoA metabolism in redox-compromised yeast cells – implications for its role in cancer chemoprevention

Abstract

Introduction: Acetyl-coenzyme A (acetyl-CoA) drives the energy-generating tricarboxylic acid (TCA) cycle in eukaryotes. Likewise, it plays an acutely important role in satisfying the high energy demands of proliferating cancer cells. Hence, we investigated the effect of aspirin, which has promising cancer-preventive properties, on acetyl-CoA metabolism using yeast cell eukaryotic models, due to their considerable advantages for laboratory research. Methods: Wild-type Saccharomyces cerevisiae EG103 and manganese-superoxide dismutase (MnSOD)-deficient EG110 yeast strains were grown in aspirin-treated and untreated ethanol medium (YPE). Microarray analysis was performed and validated by RT-qPCR and functional enzyme assays. The response to aspirin, of yeast strains with induced overexpression of alcohol dehydrogenase (ADH2), was assessed by measuring culture growth, cell viability and Adh2 enzyme activity. Results: We observed that in MnSOD-deficient yeast cells, aspirin significantly impairs transcription and activity of enzymes involved in acetyl-CoA synthesis and its transport to the mitochondria. Moreover, induced overexpression of active Adh2 enzymes, which catalyze the most upstream reaction of acetyl-CoA synthesis during growth in YPE, conferred no benefit to transformed yeast cells, failing to prevent aspirin-induced death. Conclusion: Aspirin impairs acetyl-CoA metabolism in MnSOD-deficient, redox-compromised yeast cells, causing energy failure linked to critical mitochondrial damage, resulting in apoptosis. Because core cellular processes, including apoptosis, are conserved among yeast and mammalian cells, aspirin possibly behaves similarly in early-stage cancer cells, which manifest downregulated MnSOD and are redox-compromised. Hence, this work may provide further mechanistic insight into aspirin’s chemopreventive behaviour, since acetyl-CoA is one of the least-studied targets of aspirin in its propensity to prevent cancer. Disclosures: The presented research work for part of Project ‘R&I-2015-001’ which is financed by the Malta Council for Science and Technology through the R&I Technology Development Programme.