Reprogramming Energy Metabolism In Cancer Flashcards
Recap what are the hallmarks of cancer
Including the emerging Ines
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
Which old hallmarks require reprogramming of cell metabolism in order to function
All of them
How does sustaining proliferative signalling need reprogramming cell metabolism
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
How does insensitivity to anti growth signals require a change in energy metabolism
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
How does sustained angiogenesis require changes in cellular metabolism
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
How does tissue invasion and metastasis require change in cellular metabolism
Cell movement
Production of MMPS
Requires new proteins to do so which requires more atp
How does evasion of apoptosis require changes in cellular metabolism
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
How does replicative immortality require changes in cellular metabolism
Ability to replicate indefinitely requires proteins and DNA tous le temps
What is the glycolytic switch
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
What is the Warburg effect
Describes increased lactate production by cells under aerobic conditions
It is an indicator of metabolic transformation in tumour cells
Misunderstandings about the Warburg effect
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
Health does the warburg effect and other transformed metabolic phenotypes occur
Oncogene/ TSG induced changes in proliferative drive, and direct modulation of metabolism
Glycolysis is inefficient and doesn’t produce as much energy as oxidative phosphorylation how do cancers cells compensate for this
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
PTEN
Lies downstream of many signalling pathways it is a TSG and what occurs as a result of its mutatstjon
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
When PTEN is mutated
No negative inhibition of Akt
So inc Akt activity
Inc glucose uptake
What does mutation in k Ras do
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
What does p53 do concerning cellular metabolism
It controls oxidative phosphorylation throug SCO2
It suppresses glucose uptake by inhibiting the transcription of glut1,3,4 by NK-kB
What happens when p53 is knocked out
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
When p53 is mutant
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
What does c Myc do
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
What happens to Myc in cancer cells and what is the effect
Amplified
Increase expression
Warburg effect as it increases aerobic glycolysis
What determines the metabolic changes in the cancer cells
The combination of mutations the cancers cell has
What happens with Myc amplification and TP53 mutant
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
Both TP53 and k Ras
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
Familial cancer syndrome - TCA cycle
Mutation in succiante dehydrogenase
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
Mutations in fumarate dehydrogenase
Familial causes of leiomyoma and RCC
Causes a build up of fumarate
What does the TCA cycle disruptions causes
Increase in hypoxia inducible factor which can be prooncogenic
What can HIF do
Can Dec mitochondrial respiration and increase glycolytic activity
