3.5. Cancer metabolism

Question 1

What is the Warburg Effect?

Answer 1

• It is the shift from ATP generation through oxidative phosphorylation (Kreb Cycle)
• to ATP generation through glycolysis even under normal oxygen concentrations

Question 2

Why do cancer cells switch to a less efficient form of ATP production?

Answer 2

•Lower ATP production is only a problem if glucose levels are scarce.
•Cancer cells transport greatly increased amounts of glucose into their cytoplasm and thus can still make enough ATP
•Proliferating cells have metabolic requirements that extend beyond ATP
–They need to replicate all of their cellular contents
•Nucleotides, amino acids, lipids

Question 3

Advantages of aerobic glycolysis

Answer 3

1. Glycolysis allows for shunting of carbon to other biosynthetic pathways
2. There is decreased ROS production because
   •oxidative phosphorylation is inhibited
   •there is increased production of NADPH which is involved in anti oxidant systems
   –less apoptosis initiated.
3. Increased lactate production
   •Increased lactate shuttled out of cell by MCT (monocarboxylatetransporter)•NB in angiogenesis –stimulates VEGF expression.
   •Increases tumour cell motility
   •Inhibits monocyte migration and release of TNF and IL6
   •Inhibits activation of T cells
   •Acidifies microenviromentwhich is advantageous for the tumour –increases metastasis

Question 4

Potential disadvantages of aerobic glycolysis

Answer 4

1. If high energy demands are made, they cannot produce enough ATP if not using Krebcycle.
2. If glucose not available in high enough quantities they may have to increase flux through normal ATP-generating processes.

Question 5

Why is aerobic glycolysis biosynthetic?

Answer 5

• Various glycolytic intermediates can be used for NADPH, nucleotide, amino acid and glycolipid synthesis
• Proliferating cells express the M2 form of the enzyme pyruvate kinase (PK M2)This enzyme catalysesthe production of pyruvate–This form has low activity due to phosphorylation of tyrosine amino acids within it by RTK resulting in a build –up of glycolytic intermediates which can then be used for biosynthesis.

Question 6

How is Glycolysis regulated in Proliferating Cells?

Answer 6

1. The PI3K pathway through AKT increases glycolysis by
   –Increasing glucose transporter (GLUT 4) activity –increased glucose in cell
   –Increasing hexokinase activity –phosphorylated glucose cannot move out of the cell
2. Activated Akt:
   -Activates mTORwhich increases HIF1 stability by phosphorylating HIF1α. (No longer recognisedby E3 ligase)
   •HIF1 increases glycolysis by increasing transcription of glucose transporters and glycolytic enzymes
   •HIF1 promotes pyruvate reduction to lactate by increasing transcription of lactate dehydrogenase (LDH).
   •HIF1 increases concentrations of pyruvate dehydrogenase kinase (PDK) which inhibits pyruvate dehydrogenase (PDH) thus inhibiting production of acetyl CoA and Kreb cycle
   •Thus the nett result is increased glycolysis, (as well as amino acid, lipid, nucleotide and NADPH production) with production of lactate and inhibition of Krebs cycle.

Question 7

How is this change in metabolism used for diagnostic purposes?

Answer 7

• It is used in PET scans
• PET (positron emission tomography) makes use of a radionuclide 18F (fluorine) linked to glucose forming (18F) fluorodeoxyglucose (FDG) to detect tumours.
• The FDG is injected into the patient and its accumulation in tumour cells is detected. The deoxyglucose isn’t further metabolised so it accumulates where it has been taken up.
• Remember cancer cells have increased glucose uptake compared to normal cells

Question 8

how does PET work

Answer 8

• The radionuclide (FDG) emits a positron, an antiparticle of the electron with opposite charge
• The emitted positron travels in tissue for a short distance (typically less than 1mm) during which time it loses kinetic energy, until it can interact with an electron. The encounter annihilates both electron and positron, producing a pair of gamma rays (photons) moving in approximately opposite directions.
• Photons (Gamma Rays) are detected by the scanning device.
• The position of the radionuclide (FDG) can then be plotted.
• A CT scan is done simultaneously to clearly detect the organs and skeleton of the patient.

Question 9

Uses of PET scans

Answer 9

1. To detect cancers
2. To detect if metastases have occurred
3. To determine the efficacy of treatment