Reprogramming Energy Metabolism In Cancer

Question 1

Recap what are the hallmarks of cancer

Including the emerging Ines

Answer 1

Enhance replicative potential
Evading growth suppressors 
Activating invasion and metastasis 
Enabling replicative mortality 
Inducing angiogenesis
Resisting cell death 

Evading the immune system
Reprogramming energy metabolism

Question 2

Which old hallmarks require reprogramming of cell metabolism in order to function

Answer 2

All of them

Question 3

How does sustaining proliferative signalling need reprogramming cell metabolism

Answer 3

The self sufficiency of growth signals means the cell is active all the time so needs constant energy to allow fir constitutive signalling and the growth and replication requires proteins that need to be made using ATP and nucleotides DNA needs to be made needs energy so more ATP needs to be in the cell and quickly

Question 4

How does insensitivity to anti growth signals require a change in energy metabolism

Answer 4

The new phenotype means more replication and division no cellular senescence so more energy is needed to allow this
New proteins new DNA rna need atp

Question 5

How does sustained angiogenesis require changes in cellular metabolism

Answer 5

To make new cells from the blood vessels currently there requires the production of growth signals from the tumour cells and stroma which requires energy
New endothelial cell requires proliferation

Question 6

How does tissue invasion and metastasis require change in cellular metabolism

Answer 6

Cell movement
Production of MMPS
Requires new proteins to do so which requires more atp

Question 7

How does evasion of apoptosis require changes in cellular metabolism

Answer 7

Requires a change in mitochondrial phenotype
Apoptosis needs cytochrome c
Instead the mitochondria need to hold onto the cytochrome c
Less apoptosis
Alterations in mitochondrial pathways

Question 8

How does replicative immortality require changes in cellular metabolism

Answer 8

Ability to replicate indefinitely requires proteins and DNA tous le temps

Question 9

What is the glycolytic switch

Answer 9

It is non binary it is not like oxidative phosphorylation is completely switched off and then glycolysis switches on
More glycolysis than oxidative phosphorylation in these cells regardless of the oxygen content

Question 10

What is the Warburg effect

Answer 10

Describes increased lactate production by cells under aerobic conditions
It is an indicator of metabolic transformation in tumour cells

Question 11

Misunderstandings about the Warburg effect

Answer 11

Warburg effect can never be observed in hypoxia -> this is because it is aerobic glycolysis
It does not necessarily describe increased aerobic glycolysis, which is not unique to cancer cells

Question 12

Health does the warburg effect and other transformed metabolic phenotypes occur

Answer 12

Oncogene/ TSG induced changes in proliferative drive, and direct modulation of metabolism

Question 13

Glycolysis is inefficient and doesn’t produce as much energy as oxidative phosphorylation how do cancers cells compensate for this

Answer 13

They increase their glucose uptake b upregulating transporters such as GLUT1, 2, 3,4
They also upregulate the expression of glycolytic enzymes often due to increased transcriptional activity of oncogenes

Question 14

PTEN

Lies downstream of many signalling pathways it is a TSG and what occurs as a result of its mutatstjon

Answer 14

It removes the negative feedback loop for PI3K PDK1/Akt cascade. Akt is a central metabolic regulator activated in many tumours
Its activation increases glucose uptake and regulate glycolysis
At can act to translocate the glucose transporter to the membrane
Akt also increases the ability of the cell to make biosynthetic intermediates

Question 15

When PTEN is mutated

Answer 15

No negative inhibition of Akt
So inc Akt activity
Inc glucose uptake

Question 16

What does mutation in k Ras do

Answer 16

Can also activate Akt
ALSO
K-Ras V12 Reprogram cancer cells metabolism by transforming the food source - increase activity to scavenge food from the environment
As the cancer cells grow the surrounding cells die and the cancer cells can uptake the proteins of these cells by macropinocytosis and break them down and use them as a food source
Uptake the proteins and break them down and then use them to make tumour cell proteins

Question 17

What does p53 do concerning cellular metabolism

Answer 17

It controls oxidative phosphorylation throug SCO2

It suppresses glucose uptake by inhibiting the transcription of glut1,3,4 by NK-kB

Question 18

What happens when p53 is knocked out

Answer 18

TCA cycle is non functional
The cell is no longer inhibited in its glut1,3,4
No SCO2 so no oxidative phosphorylation so cells need another way to make ATP so they do this via glycolysis

Question 19

When p53 is mutant

Answer 19

Loss of some functions but not others
Can retain ability to detox oxidative stress
TP53 is able to reduce oxidative damage caused by chemotherapy -> cancer responds less well/ does not respond to chemotherapy as it can repair DNA
RNA/DNA synthesis - faster rate of proliferation, resistance to chemotherapy induced death as can repair DNA and fix damage due to oxidative stress

Question 20

What does c Myc do

Answer 20

Transforms glutamine metabolism
Drives proliferation by increasing glucose and glutamine uptake causing production of more ATP
C Myc also drives lipogenesis, and RNA protein synthesis

Question 21

What happens to Myc in cancer cells and what is the effect

Answer 21

Amplified
Increase expression
Warburg effect as it increases aerobic glycolysis

Question 22

What determines the metabolic changes in the cancer cells

Answer 22

The combination of mutations the cancers cell has

Question 23

What happens with Myc amplification and TP53 mutant

Answer 23

Enhanced proliferation from the Myc gene and p53

Also the ability to repair and respond to oxidative stress so the cell is aggressive and unresponsive to chemotherapy

Question 24

Both TP53 and k Ras

Answer 24

K Ras mutation inc glycolysis inc Akt activity
+ inc ability to scavenge extra food from the environment
TP53 mutations increase anabolism and protect from oxidative stress
Very aggressive avascular phenotype can serve even on the remains of dead cells
Resistant to chemotherapy by anti angiogenics

Question 25

Familial cancer syndrome - TCA cycle

Mutation in succiante dehydrogenase

Answer 25

This enzyme converts succinate to fumarate in the TCA cycle
This mutation is present in lots of familial class of paraganglioma and phaechromocytoma
Causes a build up of succinate

Question 26

Mutations in fumarate dehydrogenase

Answer 26

Familial causes of leiomyoma and RCC

Causes a build up of fumarate

Question 27

What does the TCA cycle disruptions causes

Answer 27

Increase in hypoxia inducible factor which can be prooncogenic

Question 28

What can HIF do

Answer 28

Can Dec mitochondrial respiration and increase glycolytic activity