Highlights from the Literature

摘要: Tumors with high glycolytic or hypoxic properties must produce sufficient levels of acetyl-CoA to maintain cellular survival and proliferation under adverse nutrient conditions. Acetyl-CoA can be generated by oxidation glucose, glutamine, fatty acids. There are principal differences between the metabolism normal, well-fed cells tumor cells, especially nutrientdeprived Whereas former consume glucose/ pyruvate/acetyl-CoA-derived citrate synthesize acetyl-CoA, which is then used for acid cholesterol synthesis, generation nucleotides amino acids, histone acetylation, latter divert main metabolite glucose into aerobic glycolysis from pyruvate-derived mitochondrial acetylCoA lactate. The “bioenergetic substrate gap” develops when oxygen-limiting conditions ability a cell make impaired, question arises how amounts via ATP lyase produced. In brain, glial capable oxidizing acetate. an extremely elegant study, integrating observations clinical experiments, ex vivo data, preclinical mouse culture studies, Mashimo Pichumani et al Bachoo Maher laboratories showed that primary metastatic tumors growing in brain have capacity oxidize acetate while simultaneously providing explanation yet unknown carbon source critical acetyl-CoA. Previously, C-nuclear magnetic resonance analysis upon infusion C-glucose during surgery tumors, ,50% pool was derived glucose. hypothesis glioma retain acetatemetabolizing “healthy” cells. For metastases, it had been speculated microenvironment provokes change non-acetate-metabolizing organs, like lung breast, allow them metabolize their work, relevant human orthotopic models glioblastoma metastases remarkable preservation hallmark histopathological molecular features (ER-/PR-negative/Her2-positive breast cancer, EGFR/ALK/KRAS wild-type non-small VHL-nil clear renal carcinoma, BRAF melanoma) were C-NMR tissue examinations very co-infusion experiments C-acetate. Each lines oxidized but bioenergetics gap. C-acetate, distinct labeling patterns citric cycle intermediates, six patients prior treatment one line progression initial considerable, tumor-specific variable consumption demonstrated. finding validated setting infusing C-acetate operations. contrast, glutamine taken up not metabolized vivo. study published back-to-back paper, Comerford colleagues demonstrate nucleocytosolic synthetase enzyme (ACSS2) expressed has role hepatocellular gliomas, cancer utilization. Immunoreactivity ACSS2 correlated WHO grade (II-IV) reduced II/III gliomas. expression also accumulation mutation diverse genetic models. Reintroduction ACSS2-knockout embryonic fibroblasts enabled these increase incorporation glutamate. authors conclude despite extensive alterations acetate, typical at least maintained. unexpected CNS may discussed as adaptation rather more general property upregulation prerequisite convert actetate Therefore, might vulnerability specific metabolism. Further, studies summarized provide nice examples relevance research strength cross-validation.