L16 - Reprogramming Energy Metabolism in Cancer

Question 1

What is the advantage to cancer cells of utilising glycolysis over oxidative phosphorylation?

Answer 1

• Diverting carbon atoms to glycolysis enables cancer cells to produce glycolytic intermediates that can be used for biosynthetic pathways at the expense of ATP production
• This enables cancer cells to support a proliferative phenotype

Question 2

What is the Warburg effect?

Answer 2

• The Warburg effect describes an increased lactate production by cells under aerobic conditions
• It is a characteristic of cancer, as cancer cells exhibit a preference for glycolysis over oxidative phosphorylation

Question 3

List 4 oncogenes and tumour suppressor genes that modulate metabolism.

Are these genes are tumour suppressors or oncogenes?

Answer 3

1 - PTEN (tumour suppressor)

2 - p53 (tumour suppressor)

3 - c-Myc (oncogene)

4 - K-Ras (oncogene)

Question 4

What is the function of PTEN?

Answer 4

In the PI3K/AKT pathway:

• PI3K converts PIP2 into PIP3
• PIP3 activates AKT, an oncoprotein
• PTEN reconverts PIP3 into PIP2, decreasing activation of AKT
• PTEN is therefore a tumour suppressor protein

Question 5

Which oncogenic function of AKT relates to the Warburg effect?

Answer 5

• AKT activation increases glucose uptake into cells by recruiting GLUT4 to the cell membrane
• This facilitates glycolysis
• Insulin triggers the AKT pathway to bring about this effect
• Remember loss of PTEN will increase AKT activity

Question 6

List 3 mechanisms by which p53 modulates metabolism.

Answer 6

1 - p53 can block GLUT channels on the cell membrane, decreasing glucose uptake. In some cases, it is able to recruit GLUT channels

2 - p53 can stimulate oxidative phosphorylation by activating SCO2, which stimulates the synthesis of cytochrome c oxidase (COX)

3 - p53 can inhibit or stimulate glycolysis directly by acting on enzymes involved in glycolysis

*Despite being able to do the opposite in some cases, the overall function of p53 is to block glycolysis and stimulate oxidative phosphorylation

Question 7

Describe the mechanism by which c-Myc modulates metabolism.

Answer 7

c-Myc increases glycolysis:

• c-Myc increases both glucose and glutamine uptake in the cell
• Glutamine is a precursor to glutamate
• Glutamate can be converted to ketoglutarate, which is an intermediate in the Krebs cycle
• The Krebs cycle can generate PEP, which can be converted into glucose (for glycolysis), and can also generate other molecules for biosynthesis such as fatty acids, purines and heme

Question 8

Describe the mechanism by which k-Ras modulates metabolism.

Answer 8

• k-Ras upregulates GLUT1, increasing glucose uptake for glycolysis
• k-Ras also allows tumour cells to increase uptake of proteins, which can be used for biosynthesis or ATP generation

Question 9

Which combination of mutations is common in pancreatic cancer?

Answer 9

Pancreatic cancer is commonly associated with mutations in p53 and k-Ras

Question 10

List 2 enzymes involved in the Krebs cycle that can cause cancer when mutated.

With which cancers are these enzymes associated when mutated?

Describe the mechanism by which mutation of these enzymes can cause these cancers.

Answer 10

1 - Succinate dehydrogenase - paraganglioma and phaeochromocytoma

• Succinate dehydrogenase converts succinate into fumarate, transferring electrons to cytochrome c in the process. This facilitates oxidative phosphorylation
• If this process is impaired, the cell is unable to undergo oxidative phosphorylation, therefore the cell upregulates glycolysis
• Furthermore, succinate accumulates, which can enhance glycolysis by acting on hypoxia-inducible factors (HIF)

2 - Fumarate hydratase - leiomyoma and renal cell carcinoma

• Fumarate hydratase converts fumarate into malate
• If fumarate hydratase is nonfunctional, fumarate accumulates, which can enhance glycolysis by acting on hypoxia-inducible factors (HIF)