Cancer cell metabolism

Question 1

What are the 3 major metabolic fuels?

Answer 1

1. Amino acids (glutamine most abundant)
2. Carbohydrates (glucose, major nutrient and energy source)
3. Lipids (different types of lipids have different functions)

Question 2

What are the 3 stages of cell respiration?

Answer 2

1. Acetyl-CoA production (glycolysis)
2. Acetyl-CoA oxidation (TCA cycle)
3. Electron transfer and oxidative phosphorylation (electron-transfer chain)

Question 3

What are the 2 stages of glycolysis?

Answer 3

1. Preparatory phase: invest 2 ATP
2. Payoff phase: 4 ATP output

Net production of energy = 2 ATP
End product = pyruvate, can be used for TCA cycle or lactate (if no oxygen)

Question 4

What are the 3 important macromolecules from metabolites that can be created during glycolysis?

Answer 4

1. Nucleotides
2. Lipids
3. Amino acids

Question 5

Where does the TCA cycle happen, what is the starting block and why is it important?

Answer 5

In the mitochondrion
Pyruvate is processed into Acetyl-CoA
Important for anabolic hub

Question 6

Where does the electron transport chain happen, what does it consist of and what are their functions?

Answer 6

In the inner mitochondrion membrane
Constituted of 5 complexes: 1 (uses the NADH produced by the TCA cycle and processes it into NAD+), 3 and 4 pump protons in the intermembrane space; 5 uses the protons and pumps it back in the mitochondrion matrix to processes ADP into ATP

Question 7

What was Otto Warburg misinterpretation about cancer cells?

Answer 7

That they can obtain the same amount of energy from fermentation as from respiration
The truth is that the respiration is damaged in cancer cells, the mitochondria is defective

Question 8

What is the difference between normal cells and cancer cells in cell energy production?

Answer 8

In normoxia normal cells use OxPhos, but cancer cells use OxPhos and Glycolysis (lactate production)
It is wrong to say that in cancer cells OxPhos is completely deactivated
Thus cancer cells are much more flexible in oxygen privation than normal cells

Question 9

How is metabolism different in proliferating cells?

Answer 9

Non-proliferating cells require only ATP, but proliferating cells require also proteins, nucleic acids, lipids and carbohydrates => for this, changes in the glycolysis and TCA cycle occur to produce more biosynthesis to be able to produce a lot of cells
Nevertheless there is a difference in the need of normal proliferating cells and cancer proliferating cells

Question 10

What are the 3 reprogrammed metabolism involved in proliferating cells?

Answer 10

1. Altered bioenergetics (energy production)
2. Enhanced biosynthesis (building blocks)
3. Redox balance (oxidative stress)

Question 11

What is the difference in the coordination of cell growth and nutrient uptake between normal and cancer cells?

Answer 11

Normal cells need nutriments and growth factors to start proliferating
Cancer cells only need nutriments to grow, no need of extra-cellular growth factors

Question 12

What is MYC, what does it do and where is it most found (over-expressed)?

Answer 12

MYC = transcription factor
Transcribes a lot of oncogenes that regulates metabolism
MYC is over-expressed/mutated/amplified in 70% of human cancers

Question 13

How does RAS contribute to the tumor metabolic switch?

Answer 13

Ras allows a lot of protein synthesis
Increases transcription of glucose transporters
Feeds TCA cycle with glutamine

Question 14

Why do most cancer cells inactivate p53?

Answer 14

p53 drives an OXPHOS phenotype, promotes catabolic pathways and inhibits anabolic pathways => that is why most cancer cells have an inactivation of p53

Question 15

What is the use of LKB1-AMPK?

Answer 15

LKB1 = tumor suppressor, if too much ATP and not enough AMP (energetic cell) will activate AMPK and inhibit protein translation, lipid metabolism and activate autophagy

Question 16

What is the use of Rb?

Answer 16

It regulates cell cycle, inhibits E2F to transcribe the target gene and progress with cell cycle
It also inhibits indirectly the glutamine transporter into the cell

Question 17

What does mTORC1 do?

Answer 17

mTORC1 is downstream of both oncogenes and tumor suppressors: it is activated by oncogenes and inhibited by tumor suppressors
mTORC1 induces aerobic glycolysis, activates MYC and inhibits autophagy

Question 18

What are the 3 oncometabolites and what do they induce?

Answer 18

Oncometabolites = fumarate (in hyperglycemia), succinate and L-2HG (both in hypoxia)
They can induce oncogenes (metabolic rewiring and epigenetic reprogramming)

Question 19

What does HIF-a do and what is its relationship with oncometabolites?

Answer 19

HIF-a activates target genes promoting angiogenesis and cell survival
In normoxia HIF-a is inhibited, but oncometabolites are able to induce HIF-a even in normaxia

Question 20

What can be said on the heterogeneous availability of O2 and nutrients in tumor cells/tumor mass?

Answer 20

At the beginning of tumor mass, all cells are close to the blood vessels
But the more the tumor grows the more the inner cells of the tumor mass get further from the vessels and less nutriment they have
So those cells promote catabolic pathways to produce energy and survive
The outer layer of the tumor cell mass are more concentrated on proliferation

Question 21

What is the consequence of HIF-a promoting lactate production?

Answer 21

HIF-a promotes lactate production which produces NAD+ which can than be used for glycolysis and produce ATP

Question 22

Why is ROS production beneficial for cancer cells and how do they maintain the redox balance?

Answer 22

ROS production is useful for cancer cells to induce oncogenes, lose p53, etc.
They maintain redox balance by using ROS scavengers (NADPH)

Question 23

In tumor micro-environments what are the 3 ways for lactate shuttling?

Answer 23

1) Reverse Warburg effect: cancer cells produce a lot of ROS which signals normal cells to produce HIF-a (even in normoxia) which produces lactate which cancer cells use => cycle
2) Metabolic symbiosis: in solid tumor cores there is low oxygen so HIF-a and lactate production occurs, that lactate is used (and processed back to pyruvate) by the high oxygen consuming cells for OxPhos
3) Vascular endothelial lactate shuttle: endothelial cells will use the lactate produced by cancer cells and produce HIF-a which will induce angiogenesis

Question 24

Why is lactate favored by cancer cells regarding the immune system?

Answer 24

Lactate is able to down-regulate several compartments in the immune system => that is why it is favored by cancer cells

Question 25

What is the therapeutic utility of PET scans for cancer?

Answer 25

It is often used to diagnose cancer
It uses the metabolism of cancer cells to highlight them
Cancer cells use the labeled glucose which can be then seen in the scan (also possible with labeled glutamine => useful for brain cancer because cells uses mainly glutamine)