Sajnani Karishma, Islam Farhadul, Smith Robert Anthony, Gopalan Vinod, Lam Alfred King-Yin
Cancer Molecular Pathology, School of Medicine, Menzies Health Institute Queensland, Griffith University, Gold Coast, QLD, Australia.
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.
Biochimie. 2017 Apr;135:164-172. doi: 10.1016/j.biochi.2017.02.008. Epub 2017 Feb 20.
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.
癌细胞在许多细胞过程中表现出改变，包括氧感应和能量代谢。在非氧条件下的糖酵解是癌症中的主要能量产生过程，而不是像良性细胞那样通过线粒体呼吸。三羧酸循环酶的遗传和表观遗传改变有利于癌细胞从氧化磷酸化转变为无氧糖酵解。在许多癌症中都发现了编码乌头酸酶、异柠檬酸脱氢酶、琥珀酸脱氢酶、延胡索酸水合酶和柠檬酸合酶的基因突变。三羧酸循环酶的异常导致三羧酸循环中间产物（肿瘤代谢物）如2-羟基戊二酸和柠檬酸的异位产生。这些肿瘤代谢物稳定缺氧诱导因子1（HIF1）、核因子样2（Nrf2），抑制p53和脯氨酰羟化酶3（PDH3）的活性以及调节DNA/组蛋白甲基化，进而激活细胞生长信号。它们还刺激谷氨酰胺分解、糖酵解增加以及活性氧（ROS）的产生。此外，三羧酸循环酶的遗传改变与脂肪酸β-氧化增加和上皮-间质转化（EMT）诱导有关。癌症中的这些改变现象反过来可通过刺激细胞增殖和存活促进致癌作用。总体而言，三羧酸循环酶的表观遗传和遗传变化导致肿瘤代谢物中间产物的产生，这些中间产物是癌症发病机制和进展的重要驱动力。了解和应用这些机制的知识为癌症患者开辟了新的治疗选择。
