title: Genetic alterations in Krebs cycle and its impact on cancer pathogenesis.
abstract: Cancer cells exhibit alterations in many cellular processes, including oxygen sensing and energy metabolism. Glycolysis in non-oxygen condition is the main energy production process in cancer rather than mitochondrial respiration as in benign cells. Genetic and epigenetic alterations of Krebs cycle enzymes favour the shift of cancer cells from oxidative phosphorylation to anaerobic glycolysis. Mutations in genes encoding aconitase, isocitrate dehydrogenase, succinate dehydrogenase, fumarate hydratase, and citrate synthase are noted in many cancers. Abnormalities of Krebs cycle enzymes cause ectopic production of Krebs cycle intermediates (oncometabolites) such as 2-hydroxyglutarate, and citrate. These oncometabolites stabilize hypoxia inducible factor 1 (HIF1), nuclear factor like 2 (Nrf2), inhibit p53 and prolyl hydroxylase 3 (PDH3) activities as well as regulate DNA/histone methylation, which in turn activate cell growth signalling. They also stimulate increased glutaminolysis, glycolysis and production of reactive oxygen species (ROS). Additionally, genetic alterations in Krebs cycle enzymes are involved with increased fatty acid β-oxidations and epithelial mesenchymal transition (EMT) induction. These altered phenomena in cancer could in turn promote carcinogenesis by stimulating cell proliferation and survival. Overall, epigenetic and genetic changes of Krebs cycle enzymes lead to the production of oncometabolite intermediates, which are important driving forces of cancer pathogenesis and progression. Understanding and applying the knowledge of these mechanisms opens new therapeutic options for patients with cancer.
authors.affiliation: Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Karishma
authors.initials: K
authors.lastname: Sajnani
authors.affiliation: Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia; Department of Biochemistry and Molecular Biology, University of Rajshahi, Rajshahi, 6205, Bangladesh.
authors.forename: Farhadul
authors.initials: F
authors.lastname: Islam
authors.affiliation: Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia; Genomics Research Centre, Institute of Health and Biomedical Innovation, Faculty of Health, Queensland University of Technology, Brisbane, Queensland, Australia.
authors.forename: Robert Anthony
authors.initials: RA
authors.lastname: Smith
authors.affiliation: Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia.
authors.forename: Vinod
authors.initials: V
authors.lastname: Gopalan
authors.affiliation: Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia. Electronic address: a.lam@griffith.edu.au.
authors.forename: Alfred King-Yin
authors.initials: AK
authors.lastname: Lam
mesh_terms: D000818:Animals; D002952:Citric Acid Cycle / Q000502:physiology*; D006801:Humans; D051793:Hypoxia-Inducible Factor 1 / Q000378:metabolism; D009154:Mutation; D051267:NF-E2-Related Factor 2 / Q000378:metabolism; D009369:Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D051793:Hypoxia-Inducible Factor 1; D051267:NF-E2-Related Factor 2; D017382:Reactive Oxygen Species
keywords: Cancer metabolism; Krebs cycle; Mitochondria; Mutations; Oncometabolites; TCA cycle