L17: Reprogramming Energy Metabolism In Cancer Flashcards
What are the 6 hallmarks of cancer
Sustaining proliferative signalling Evading growth suppressors Resisting cell death Activating invasion and metastasis Inducing angiogenesis Enabling replicative immortality
What are the 4 other hallmarks added to the 6 hallmarks
Deregulating cellular energetic
Avoiding immune destruction
Genome instability and mutations
Tumour promoting inflammation
What is required to permit the cancer hallmarks
Metabolic transformation
What are the 3 nutrients for a cell metabolism
Lipids
Carbs
Proteins
What are lipids important in
Cell membrane and energy
What is carbs used for
Produce DNA, proteins, cell membrane and energy
What are proteins used
Brocken into amino acids to produce DNA and energy
In normal cells how is energy obtained in aerobic conditions
1) glycolysis: glucose is converted to pyruvate
2) TCA cycle: Pyruvate is metabolised
How many energy i.e ATP is obtained from a normal cell in arerobic condition
36 ATP
How does a normal cell obtain energy in anaerobic conditions
Glycolysis occurs only
In cancer how is energy metabolised
Using glycolysis only even in aerobic condition
At what rate does glycosis in cancer cells run
Fast
What is the Warburg effect in cancer
when cancer cells switch to glycolysis which occurs in aerobic conditions and produces the breakdown product of lactate as a result
What also the Warburg effect in cancer to take place
Activation of oncogenes and/or loss of tumour suppressor genes
What is the role of PTEN
To inhibit the PI3K pathway and stop cell survival and proliferation
To make PI3K pathway occur in cancer what can happen to PTEN
Mutates to remove its effect
If PTEN is removed what protein is activated that removes inhibitory apoptosis protein from BAD so apoptosis is inhibited
AKT
What other role does active AKT have
- Increases glucose uptake by increasing GLUT-4 on the cell surface
- Increase the rate of glycolysis by activating the enzyme PFK
What are the other way in activating akt
Mutation of RAS
What is the normal role of P53 in terms of glycolysis and oxidative phosphorylation
P53 decreases glycolysis and increases oxidative phosphorylation = opposes effect of the Warburg effect
What does P53 help maintain
The mitochondria
How does P53 maintain oxidative phosphorylation
By transcription and activation of SC02 which is a regulator of cytochrome c oxidase complex in the electron transport chain
What can happen to P53 in tumours
Deficienct i.e knocked out
Mutated
What happens if P53 is knocked out
TCA is not functional and glycolysis occurs= Warburg effect
What happens if P53 is mutated instead
It will retain its ability to up regulate enzymes involved in:
1) detox oxidative stress
2) dna/rna synthesis
3) oxidative atp generation
4) increased glucose consumption
What does normal P53 do to the uptake of glucose
Inhibit the uptake of glucose by inhibiting transcription of glut 1 and glut 4 and glut 3
What is c-MHC
A gene
What does c-myc regulate
Lipogenesis
Ribosome genesis
Glycolysis
Glutamineloysis
If c-myc is amplified in cancer what does it become
An oncogenes
What does amplification of c-myc mainly lead to
Glutamineolysis
What is glutamineolysis
Glutamine metabolism
What does glutamine metabolism allow in the cancer cell
Produce many bio synthetic intermediates to help drive cell proliferation
How does K-RAS mutation change metabolism of cancer cells
- Increase uptake of proteins- used to generate new proteins e.g DNA and RNA
- permanently activate AKT which increases glycolysis
In familiar cancer syndrome what happens
Enzymes involved in the TCA cycle can become mutation
What does mutations of enzymes in the TCA cycle lead to
HIF activation
What does HIF activate
Angiogenesis
Proliferation
Cell survival
Increased glycolysis
