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Role of reactive oxygen species in modulating carbohydrate metabolism in acute myeloid leukaemia

Robinson, Andrew 2017. Role of reactive oxygen species in modulating carbohydrate metabolism in acute myeloid leukaemia. PhD Thesis, Cardiff University.
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Abstract

Reactive oxygen species (ROS) are known to play a significant role in cellular signalling pathways, associated with growth, differentiation and survival and in many cancers, elevated ROS levels have been linked with aberrant signalling. Previously, we showed that human haematopoietic progenitor cells expressing mutant RAS (a common abnormality in AML) had elevated NOX2 derived ROS which led to increased cell proliferation. However, it is currently unknown how ROS mediates these effects. Previous preliminary data suggests significant ROS attributable gene changes are associated with glycolysis, a feature also common in solid tumours. Using human haematopoietic progenitor cells, it is reported here for the first time that, elevated ROS leads to changes in extracellular lactate production and increases in glucose uptake. Furthermore, modulation of ROS levels in AML cell lines also generate results consistent with a ROS induced model of increased glycolysis. Gene expression profiling identified ROS related changes in specific glycolytic enzymes, whilst immunoblotting verified ROS dependent increases in protein expression of a key regulatory glycolytic enzyme, 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase 3 (PFKFB3), in both human cells and AML cell lines. Metabolomic analysis using mass spectrometry, was performed on AML cell lines in which ROS levels were manipulated and AML patient samples were characterised according to ROS production. This revealed changes in concentrations of metabolites associated with glycolysis and metabolic pathways important in ROS regulation. Modulation of PFKFB3 expression generated changes in glucose uptake consistent with ROS mediated changes in this enzyme. In summary, this study establishes for the first time that increased ROS production in AML models leads to increased glycolysis and metabolic reprogramming as a consequence of modulation of PFKFB3 expression by ROS.

Item Type: Thesis (PhD)
Status: Unpublished
Schools: Medicine
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
Date of First Compliant Deposit: 10 January 2018
Last Modified: 08 May 2019 02:00
URI: http://orca-mwe.cf.ac.uk/id/eprint/108022

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