Reprogramming energy metabolism

Question 1

Mutations of genes can change a cell’s phenotype from proliferative to invasive, what else may these mutations cause?

Answer 1

Alteration in metabolism to facilitate growth. Can affect surrounding nonmalignant cells.

Question 2

What determines how a cancer responds to therapy?

Answer 2

Glucose limitation - may be an area for control

Question 3

Why is metabolic transformation needed?

Answer 3

To permit cancer hallmarks

Question 4

What does self sufficiency in growth signals and insensitivity to antigrowth signals require?

Answer 4

In order to proliferate it requires new proteins, DNA, RNA and ATP which needs a large metabolic input and double the energy for a cell to divide.

Question 5

What does sustained angiogensis require?

Answer 5

New endothelial cell proliferation and surbial in hypoxia. Requires glycolytic ATP generation, new proteins and DNA

Question 6

What does a cell need to do to evade apoptosis?

Answer 6

Requires alteration of mitochondrial phenotype through the metabolic pathways so that they are less likely to respond to chemo as chromosome C isn’t released.

Question 7

What is replicative immortality?

Answer 7

The ability to replicate indefinitely

Question 8

What nutrients do cancers require?

Answer 8

Lipids - FA for cell membranes and energy
Sugars - DNA, proteins, cell membrane and energy
Protein - Proteins, DNA and energy

Question 9

What is the glycolytic switch?

Answer 9

Change from aerobic respiration to anaerobic. The switch causes a shift in the ration between the two types as both are always active.

Question 10

How many ATP are produced by aerobic and anaerobic?

Answer 10

Aerobic = 2 ATP
Anaerobic = 1 ATP and 1 lactate
For every glucose metabolised to pyruvate it requires 1 ATP but produces 2. Pyruvate will then go on to produce lactate or enter mitochondria for oxidative phosphorylation.

Question 11

Why do treatments that target highly proliferating cells cause side effects?

Answer 11

The metabolism of a normal and a cancer cell are not that different, so the treatment is targeting normal cells too.

Question 12

What is the main difference between a cancer and a normal cell?

Answer 12

Cancer cells have increased glycolysis due to an increase in glycolytic intermediate synthesis pathways.

Question 13

Why does glycolysis increase in a cancer cell?

Answer 13

Pyruvate mainly goes to lactate and only a little to mitochondria. As not all the glucose goes on to make ATP but gets channelled into biosynthetic intermediates to help proliferation, the cell must take up more glucose to compensate. Cancer cells require more glucose to make the dame amount of ATP as a normal cell.

Question 14

What intermediates are produced whilst getting glucose into the cell and what are they used for?

Answer 14

Fructose-6-phosphate and glucose-6-phosphate are used to make nucleotides

Question 15

What is glycerol-3-phosphate used for?

Answer 15

To make lipid molecules for the cell membrane.

Question 16

Why does a cancer cell need more glucose than a normal cell?

Answer 16

Due to their continuous proliferation and formation of cellular components that require a C to be diverted away from glycolysis and into the intermediate pathways.

Question 17

What is the Warburg effect?

Answer 17

The increase in lactate production by cells under aerobic conditions. It is aerobic lactate production not glycolysis. The theory suggests that the effect can never be seen in hypoxia and it doesn’t describe an increase in aerobic glycolysis as it is not unique to cancer cells.
Independent to O2 conditions.

Question 18

What is an increase in lactate production and indicator of?

Answer 18

Metabolic transformation in the cells.

Question 19

How can the metabolism be altered?

Answer 19

Through oncogenes, TSG induced changes in proliferative drive and direct modulation of metablism

Question 20

What is PTEN?

Answer 20

PTEN is downstream of RTK to control the activity of AKT by inhibiting.

Question 21

What happens if PTEN is mutated?

Answer 21

There is loss of inhibition and so PI3 kinase activity increases and leads to continuous activation of AKT. Increased glucose uptake and glycolysis = increased ability to make biosynthetic intermediates and produce ATP for proliferation.

Question 22

What does active AKT do?

Answer 22

Translocates glucose transporters on the membrane to increase capacity to take up glucose and help the cell proliferate.

Question 23

How is the maximum rate of glucose transport reached?

Answer 23

Glucose transporters are diffusion limited so as long as there is enough concentration of glucose outside of the cell, maximum transport is achieved.

Question 24

What is the advantage to a cancer cell of increasing glucose transport capacity?

Answer 24

Increased channels = increased uptake = quicker use of glucose = proliferate quicker

Question 25

What effect does AKT have on the rate limiting step of glycolysis?

Answer 25

AKT increases PFK activity to increase rate of glycolysis.

PFK normally limits rate

Question 26

What modulatory role does p53 play in glycolysis?

Answer 26

TF for proteins hexokinase, TIGAR and PGM. It control SCO2.

Question 27

What happens if p53 is absent?

Answer 27

Biosynthetic pathways are enhanced. No upregulation of SCO2 so inefficient ETC. The cell relies more on glycolysis producing lactate = Walberg effect

Question 28

Why is SCO2 needed?

Answer 28

SCO2 is required for putting together parts of the ETC for oxidative phosphorylation in mitochondria.

Question 29

What is p53 is mutated?

Answer 29

Retains some function for upregulating enzymes and biosynthetic processes. e.g. DNA/RNA synthesis, increase glucose consumption, detox oxidative stress. SCO2 activity retained so ATP is made via oxidative phosphorylation.

Question 30

Why is SCO2 important?

Answer 30

Allows the cell to proliferate at a higher rate and maintains the ability to make ATP via ETC. The cell is less reliant on glycolysis and less lactate is produced so cells can do everything quicker = more aggressive

Question 31

What is the effect of c-myc mutation and what adaptations does the cell need to make?

Answer 31

When c-Myc, an oncogene, is amplified it drives more proliferation. But this requires an increase in metabolism so the cell increases glutamine metabolism to power the mitochondria.

Question 32

Where is glutamine obtained from?

Answer 32

High concentration in the blood that is used after glucose

Question 33

How does c-Myc amplification drive faster proliferation?

Answer 33

Binds to E boxes to directly stimulate ribosomal mass and translate RNA quicker.

Question 34

What is the benefit to the cell of giving the TCA cycle glutamine?

Answer 34

Glutamine in TCA allows synthesis of other products involved in cell structure e.g. Fa, sterols, purines, AA, pyrimidines

Question 35

What is the metabolic phenotype of a tumour dependent on?

Answer 35

The combination of mutations and amplifications. TSG and oncogenes work together to increase proliferation, ATP production and glycolysis.

Question 36

What benefits does k-Ras mutation provide a cancer cell?

Answer 36

• Transforms the food source. If the cell is starved it will result in aggressive macropinocytosis of the surrounding environment. The cells will gain proteins and nutrients without being dependent on ATP for the generation of new structures.
• Increases glycolysis through AKT activation

Question 37

Why is pancreatic cancer so aggressive?

Answer 37

Presence of both Tp53 and k-Ras mutations to increase glycolysis, pinocytosis, increase anabolism and protect against oxidative stress and toxins.

Question 38

What does mitochondrial dysfunction lead to?

Answer 38

Tumourgenesis

Question 39

Give an example of a deficiency in the TCA cycle that leads to mitochondrial dysfunction.

Answer 39

Succinate dehydrogenase deficiency = paraganglioma

Fumarate hydratase deficiency = RCC

Question 40

What is the role of succinate?

Answer 40

Plays a role in both TCA and ETC but can cope without it.

Question 41

In which two cell types can the cells survive with loss of both Succinate and Fumarate?

Answer 41

Paraganglia in sympthetic NS

Chromaffin cells of adrenal medulla

Question 42

What can all other cells withstand?

Answer 42

A heterogenity loss but cannot survive with a loss of both