Reprogramming energy metabolism in cancer

Question 2

What are the 6 hallmarks of cancer

Answer 2

1. Sustaining proliferative signalling – cancer cells stimulate their own growth.
2. Evading growth suppressors – cancer cells resist inhibitory signals that might stop cell growth.
3. Resisting cell death – evade apoptosis.
4. Enabling replicative immortality – cancer cells have a limitless replicative potential.
5. Inducing and sustaining angiogenesis – stimulation of growth of blood vessels to get better nutrient supply to tumour.
6. Activating invasion and metastasis – spreads the cancer to distant sites.

Question 3

What are the updated 2 added hallmarks of cancer?

Answer 3

1. Abnormal metabolic pathways – cancer cell metabolism is shifted towards provision of cellular building blocks and less efficient ATP production, combined with mitochondrial deactivation.
2. Immune system evasion – cell avoids immune destruction.

Question 4

What are the 2 updated enabling characteristics of cancer?

Answer 4

1. Genome instability and mutation.
2. Tumour-promoting inflammation.

Question 5

What are the metabolic transformations required to permit the hallmarks of cancer?

Answer 5

Refer to the provided images for detailed metabolic transformations.

Question 6

What are the 3 categories we can divide nutrients we eat into + what are they important for?

Answer 6

1. Lipids: Important for cell membranes and energy production.
2. Carbohydrates: Important for DNA/RNA, proteins, cell membranes, and energy production.
3. Proteins: When eaten, they are digested into amino acids/small peptides, which can be used to make new proteins, DNA, or energy.

Question 7

What is glycolysis?

Answer 7

Glycolysis is the conversion of glucose into pyruvic acid (1 molecule of glucose → 2 molecules of pyruvate).

Question 8

What is the first stage of glycolysis called?

Answer 8

The first stage is called the preparatory stage.

Question 9

What are the end products of glycolysis?

Answer 9

End products: 2 ATP, 2 NADH, and 2 pyruvate molecules. NADH is fed into the electron transport chain where it regenerates itself into NAD+ and produces more ATP, which requires oxygen.

Question 10

What needs to happen in O2 is insufficient during glycolysis?

Answer 10

If O2 is insufficient, NAD+ has to be regenerated by fermentation processes such as conversion of pyruvic acid into lactate (lactate produced in hypoxic conditions).

Question 11

What is fermentation in cancer?

Answer 11

Fermentation is what happens in cancer cells, where there is increased glucose uptake and glycolysis runs at a much higher rate to produce ATP and divert glycolytic intermediates to biosynthetic pathways.

Question 12

What is the trade-off between energy and macromolecule production in cancer cells?

Answer 12

Because cancer cells proliferate so fast, there is a trade-off between energy production and production of macromolecules. Cancer cells divert carbons to macromolecule biosynthesis, sacrificing ATP production.

Question 13

What is the take-home message regarding cancer cell metabolism?

Answer 13

Cancer cells need to support a proliferative phenotype by diverting carbon atoms to biomass production (cellular building blocks), sacrificing energy production. This is known as the Warburg effect.

Question 14

What is the Warburg effect?

Answer 14

The Warburg Effect describes an increased lactate production by cells under aerobic conditions.

Question 15

What are some misunderstandings about the Warburg effect?

Answer 15

1. Warburg Effect can never be observed in hypoxia. Under hypoxia, normal cell behavior is to produce lots of lactate.
2. It does not necessarily describe increased aerobic glycolysis, which is not unique to cancer cells.

Question 16

Why is the Warburg effect discussed?

Answer 16

We observe increased lactate production in cancer cells and in most tumours, indicating metabolic transformation of tumour cells.

Question 17

Where does PTEN activity lie?

Answer 17

PTEN activity lies downstream of many signalling pathways.

Question 18

What does PTEN stand for?

Answer 18

PTEN: Phosphatase and Tensin homolog deleted from C10.

Question 19

What is the role of PTEN?

Answer 19

PTEN is a phosphatase that negatively regulates the PI3K-AKT pathway.

Question 20

What happens if we lose PTEN?

Answer 20

If we lose PTEN, the PI3K-AKT pathway can become activated, supporting cell survival, proliferation, and invasion.

Question 21

What does AKT activation result in?

Answer 21

AKT activation increases glucose uptake via translocation of GLUT glucose transporters from cytoplasmic vesicles to the cell membrane surface.

Question 22

What is the role of AKT in glycolysis?

Answer 22

AKT activates the enzyme phosphofructokinase, which is the pace setter for glycolysis, making glycolysis happen faster.

Question 23

What are the take-home messages about PTEN?

Answer 23

1. PTEN acts as a tumour suppression gene.
2. Activation of the AKT signalling pathway occurs through loss of PTEN activity.
3. AKT promotes proliferation, cell migration, and survival.

Question 24

What is the role of p53 in relation to the Warburg effect?

Answer 24

P53, a central metabolic regulator, increases oxidative phosphorylation, opposing the Warburg effect.

Question 25

How does P53 oppose the Warburg effect?

Answer 25

P53 inhibits glycolysis and helps maintain mitochondria, driving oxidative phosphorylation.

Question 26

What does p53 control oxidative phosphorylation through?

Answer 26

p53 controls oxidative phosphorylation through SCO2.

Question 27

Why do cancer cells show a reduced dependence on oxidative phosphorylation?

Answer 27

The reduced dependence is not due to defects in TCA cycle components but reflects an ability of proteins associated with oncogenic transformation to promote glycolysis.

Question 28

What is the role of SCO2?

Answer 28

SCO2 is involved in the assembly of the copper A site in cytochrome c oxidase, which is important for oxidative phosphorylation.

Question 29

What do p53 deficient tumours exhibit?

Answer 29

P53 deficient tumours exhibit the Warburg Effect due to mitochondrial deactivation and less inhibition of glycolysis.

Question 30

What happens if TP53 is mutated instead of knocked out?

Answer 30

Retention of its ability to upregulate enzymes involved in detoxifying oxidative stress, DNA/RNA synthesis, oxidative ATP generation, and increased glucose consumption.

Question 31

What is c-Myc's role?

Answer 31

c-Myc transforms glutamine metabolism and regulates genes involved in lipogenesis, ribosome biogenesis, glycolysis, and glutaminolysis.

Question 32

What happens if TP53 is mutated instead of knocked out?

Answer 32

Retention of its ability to upregulate enzymes involved in detox oxidative stress, DNA/RNA synthesis, oxidative ATP generation, and increased glucose consumption.

Question 33

What is the role of c-Myc?

Answer 33

c-Myc transforms glutamine metabolism and regulates genes involved in lipogenesis, ribosome biogenesis, glycolysis, and glutaminolysis.

Question 34

What normally happens to c-Myc in tumours?

Answer 34

Myc amplification is often observed in tumours, which increases the expression of Myc target genes.

Question 35

Why is c-Myc amplification so good at driving proliferation?

Answer 35

c-Myc amplification drives proliferation by supporting metabolism needed for generating a proliferative phenotype, especially through glutaminolysis.

Question 36

What does the metabolic phenotype of a tumour depend on?

Answer 36

The metabolic phenotype of a tumour depends on the combination of mutations.

Question 37

What do K-Ras mutations transform?

Answer 37

K-Ras mutations transform the food source, inducing tumour cells to increase uptake of external protein, which can be used to generate new proteins, ATP, and DNA/RNA.

Question 38

What type of mutations occur in pancreatic cancer and what do they contribute towards?

Answer 38

Pancreatic cancer contains both TP53 and K-RAS mutations, which contribute to increased glycolysis and the ability to scavenge food from the environment.

Question 39

What are examples of familial cancer syndromes illustrating the role of metabolism in cancer?

Answer 39

Mutations in Succinate dehydrogenase result in Paraganglioma and pheochromocytoma, while mutations in Fumarate hydratase result in Leiomyoma and renal cell carcinoma.

Question 40

Describe the electron transport chain.

Answer 40

Complex 2 serves as an entry point into the electron transport chain, accepting electrons from FADH2, while complex 1 accepts electrons from NADH.

Question 41

Which metabolites can disrupt normal cell signalling processes?

Answer 41

Blockages in fumarate hydratase or succinate dehydrogenase lead to the accumulation of fumarate or succinate, activating HIF and increasing glycolysis, cell proliferation, and survival.

Question 42

What is a summary of mutations and their metabolic consequences?

Answer 42

Accumulation of fumarate and succinate inhibits prolyl-hydroxylases, keeping HIF activated, while MYC increases glucose uptake and AKT activates glycolysis bottleneck reactions.