Metabolic Adaptation of Cancer Cells

Question 1

What is (18)F-FDG?

Answer 1

2-deoxy-2-(18)fluoro-D-glucose

• Contains radioactive fluoride
• Glucose can’t be further metabolised

Question 2

Which cell type have a high capacity to take up (18)F-FDG?

Answer 2

Tumour cells

Question 3

How does positron emission tomography (PET) detect tumour cells that have taken up (18)F-FDG?

Answer 3

Radioactive decay of fluoride releases gamma rays

Detected by PET

Question 4

What is the Warburg effect?

Answer 4

Most cancer cells shift from ATP generation through oxidative phosphorylation to glycolysis, even under normal oxygen concentrations

Question 5

What are the consequences of the Warburg effect?

Answer 5

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

Question 6

How does the lactate produced by cancer cells change the environment around it?

Answer 6

More acidic > may stimulate neovascularisation

Question 7

How do cancer cells accumulate large amounts of glucose?

Answer 7

Hyperactivity of GLUT1

Question 8

What is the major end point of glucose metabolism in cancer cells under aerobic conditions?

Answer 8

Glycolysis, making lactate

Question 9

How is glycolysis re-engineered in cancer cells?

Answer 9

Over-expression of GLUT1
Glycolytic enzymes over-expressed
- Hexokinase
- PFK1
- Lactate dehydrogenase
Over-expression of pyruvate kinase M2 (PKM2)

Question 10

What is PKM2?

Answer 10

Foetal isoform of pyruvate kinase with lower activity

Question 11

Expression of which enzymes is induced by hypoxia in cancer cells, allowing them to do what?

Answer 11

Expression of
- Glycogen phosphorylase
- Glycogen synthase
Can store and use glycogen

Question 12

In the early stage of tumour development, which cells in the mass are most hypoxic?

Answer 12

Those in centre

Question 13

Why does (18)F-FDG accumulate in cancer cells?

Answer 13

Enhanced uptake via over-expressed GLUT1

Inability of PFK-1 to further metabolise it in glycolysis

Question 14

Does the production of ROS in the mitochondria occur in cancer cells under hypoxic conditions?

Answer 14

Yes

Question 15

If p53 doesn’t work, can ROS activate other tumour suppressor proteins?

Answer 15

Yes

Question 16

What are the metabolic challenges of cancer cells?

Answer 16

Oxidative stress caused by over-production of ROS in hypoxia
Need precursors and reducing power for synthesis of
- Membrane lipids
- Proteins
- Nucleic acids

Question 17

What are the solutions for the metabolic challenges of cancer cells?

Answer 17

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

Question 18

What is glutathione?

Answer 18

Antioxidant tripeptide

Question 19

What is the relationship between NADPH and antioxidants, including glutathione?

Answer 19

Regeneration of oxidised antioxidants, including glutathione

Question 20

How is NADPH generated?

Answer 20

In cytosol mainly in pentose phosphate pathway

Question 21

What is the role of the pentose phosphate pathway?

Answer 21

Generate NADPH for use in biosynthesis of fatty acids, proteins, amino acids, and nucleic acids
Generate NADPH for regeneration of oxidised antioxidants

Question 22

What are the two phases of the pentose phosphate pathway?

Answer 22

Oxidative generation of NADPH

Non-oxidative inter-conversion of sugars

Question 23

How does the non-oxidative inter-conversion of sugars in the pentose phosphate pathway contribute to the synthesis of amino and nucleic acids?

Answer 23

Generates variety of carbon backbones

Needed for amino and nucleic acids

Question 24

What is the relationship between glycolysis and the pentose phosphate pathway?

Answer 24

Intermediates of glycolysis in excess because of slow PKM2

Can enter pentose phosphate pathway

Question 25

What is the glucose-6-phosphate generated from glycolysis used for in cancer cells?

Answer 25

Pentose phosphate pathway

Question 26

What are some metabolic approaches to treat cancer?

Answer 26

Dietary restriction to limit glucose availability
Inhibitors of glycogen phosphorylase
Inhibitors of hexokinase
Inhibitors of PKM2