Metabolic Adaptation of Cancer Cells Flashcards
What is (18)F-FDG?
2-deoxy-2-(18)fluoro-D-glucose
- Contains radioactive fluoride
- Glucose can’t be further metabolised
Which cell type have a high capacity to take up (18)F-FDG?
Tumour cells
How does positron emission tomography (PET) detect tumour cells that have taken up (18)F-FDG?
Radioactive decay of fluoride releases gamma rays
Detected by PET
What is the Warburg effect?
Most cancer cells shift from ATP generation through oxidative phosphorylation to glycolysis, even under normal oxygen concentrations
What are the consequences of the Warburg effect?
Cancer cells derive most of their energy from aerobic glycolysis
Accumulate (18)F-FDG (and glucose)
Reduced rate of pyruvate metabolism in TCA cycle and oxidative phosphorylation
How does the lactate produced by cancer cells change the environment around it?
More acidic > may stimulate neovascularisation
How do cancer cells accumulate large amounts of glucose?
Hyperactivity of GLUT1
What is the major end point of glucose metabolism in cancer cells under aerobic conditions?
Glycolysis, making lactate
How is glycolysis re-engineered in cancer cells?
Over-expression of GLUT1 Glycolytic enzymes over-expressed - Hexokinase - PFK1 - Lactate dehydrogenase Over-expression of pyruvate kinase M2 (PKM2)
What is PKM2?
Foetal isoform of pyruvate kinase with lower activity
Expression of which enzymes is induced by hypoxia in cancer cells, allowing them to do what?
Expression of
- Glycogen phosphorylase
- Glycogen synthase
Can store and use glycogen
In the early stage of tumour development, which cells in the mass are most hypoxic?
Those in centre
Why does (18)F-FDG accumulate in cancer cells?
Enhanced uptake via over-expressed GLUT1
Inability of PFK-1 to further metabolise it in glycolysis
Does the production of ROS in the mitochondria occur in cancer cells under hypoxic conditions?
Yes
If p53 doesn’t work, can ROS activate other tumour suppressor proteins?
Yes
What are the metabolic challenges of cancer cells?
Oxidative stress caused by over-production of ROS in hypoxia
Need precursors and reducing power for synthesis of
- Membrane lipids
- Proteins
- Nucleic acids
What are the solutions for the metabolic challenges of cancer cells?
Warburg effect reduces use of TCA cycle > less ROS
Synthesis of more anti-oxidants to scavenge ROS
Increased influx for glycolysis and pentose phosphate pathways > production of precursors and NADPH > synthesis
What is glutathione?
Antioxidant tripeptide
What is the relationship between NADPH and antioxidants, including glutathione?
Regeneration of oxidised antioxidants, including glutathione
How is NADPH generated?
In cytosol mainly in pentose phosphate pathway
What is the role of the pentose phosphate pathway?
Generate NADPH for use in biosynthesis of fatty acids, proteins, amino acids, and nucleic acids
Generate NADPH for regeneration of oxidised antioxidants
What are the two phases of the pentose phosphate pathway?
Oxidative generation of NADPH
Non-oxidative inter-conversion of sugars
How does the non-oxidative inter-conversion of sugars in the pentose phosphate pathway contribute to the synthesis of amino and nucleic acids?
Generates variety of carbon backbones
Needed for amino and nucleic acids
What is the relationship between glycolysis and the pentose phosphate pathway?
Intermediates of glycolysis in excess because of slow PKM2
Can enter pentose phosphate pathway
What is the glucose-6-phosphate generated from glycolysis used for in cancer cells?
Pentose phosphate pathway
What are some metabolic approaches to treat cancer?
Dietary restriction to limit glucose availability
Inhibitors of glycogen phosphorylase
Inhibitors of hexokinase
Inhibitors of PKM2
