Metabolism in cancer cells Lecture 12

Question 1

Why is cancer metabolism different?

Answer 1

Increased proliferation- need nucleotides, AAs, lipids, ATP, redox active molecules

Mutations in signalling pathways

Detoxification of anticancer therapies - resistance to cancer therapies

Survival in an inhospitable environment - hypoxic envirnments due to low levels of blood vessels

Question 2

What is the Warburg effect?

Answer 2

High lactate production even in the presence of oxygen- aerobic respiration

Rapid rate of lactate production produces an acidic environment and can increase invasion

In an hypoxic environment, the TCA cycle cant happen anymore, therefore 2 pyruvate is made from 1 glucose. Also 2 molecules of NAD+ are converted into NADH. NADH is normally regenerated, but if there is not enough oxygen pyrubate is reduced to lactate and NADH is oxdised to NAD+ to keep glycolysis running. - Cancer cells do this under normal conditions.

Can be used for tumour diagnosis- FDG-PET imaging

Question 3

What are the possible explanations for high rates of glycolysis in normoxic conditions in cancer cells?

Answer 3

Hypotheses:

1. Mitochondrial energy generation is irreversibly damaged (some cancers exhibit mutations in TCA cycle enzymes eg pheochromocytoma)
2. Changes in expression of metabolic enzymes (c-Mycn increases glutamate uptake, p53increases redox and PTEN increases glucose transporters and therefore glycolysis, all mutated in a high percentage of cancers)
3. Altered metabolic requirements (G6p turned to nucleotides, G3P turned into lipids) - needs to support a proliferative phenotype to orm sucessful cancer cells

Question 4

Describe 5-FU

Answer 4

5-fluorouracil disrupts nucleotide synthesis by blocking thymidylate synthase

Thyminylate synthase is also part of the pathway to synthesis dTTP

May also ellicit a DNA damage response by being incorporated into DNA and RNA

But has side effects - effects fast dividing cells of the body (hair, skin, GI tract)

Question 5

Describe the hypoxia phenotype in cancer cells

Answer 5

Tumours are poorly vascularised which leads to hypoxic conditions. This causes:

• Slower division (counterproductive to targeting fast dividing cells)
• Increased cell migration (can no longer use radiotherapy)
• Increased survival factors
• Changes in cellular metabolism

Slower proliferation

Increased cell migration - promote metastasis

Increase survival factors (in non-severe hypoxia)

Chromatin silencing in areas

Change in cellular metabolism (autophagy)

Reduced differentiation profile

Can result in therapy resistance

Can target the H+/Na+ antiporter to prevent the H+ getting out and lowring the ph, killng the cell.

Question 6

Describe pyruvate kinase as a novel therapeutic target

Answer 6

Conversion of phosphoenolpyruvate to pyruvate

M1 is expressed in diffrentiated, non-proflierating cells

Isoform M2 is expressed in proliferating embryonic cells

Helps tumours

Can be targeted but tumours find away around it

Question 7

Could lactate dehydrogenase be a therapeutic target?

Answer 7

Required for NAD+ regeneration for continued glycotic activty LDH5 often observed in cancer cells

Tumours stop proliferating

Question 8

Describe extracellular acidifaction and off target effects

Answer 8

High intracellular lactate would result in intracellular drop and a resultng inhibition of glycolysis

Cells pump lactate and proton out using monocaeboxylate transporters

Extracellular carbonic anhydrases act to make bicarbonate

Na+/H+ exchanger antiports proton and Na+ ions to reduce intracellular proton concentration. .

Off target effects include - muscle activty (have to be able to expell lactate into blood stream so cant block lactate) , brain fucntion (need LDH), kidney fucntion (need Na+/H+ antiporters)

Question 9

Describe use of amino acids as therapeutic targets

Answer 9

Glutamine, asparagine and arginine are good targets

INjection with argnine deiminase degrades plasma arginine - casues reduced tumour growth by 50% in mouse models.