Lecture 12 - Reprogramming Energy Metabolism in Cancer NOT FINISHED Flashcards
Metabolic transformation is required to permit all cancer hallmarks:
List the hallmarks and their metabolic implications
- self sufficiency in growth signals –> proliferation –> new proteins, DNA, RNA and ATP
- insensitivity to anti-growth signals –> proliferation –> new proteins, DNA, RNA and ATP
- sustained angiogenesis –> new endothelial cells proliferation, survival in hypoxia –> glycolytic ATP generation, new proteins DNA
- tissue invasion and metastases –> cell movement, production of MMPs –> new proteins, ATP
- evasion of apoptosis –> change in mitochondrial phenotype –> alterations in mitochondria metabolic pathways
- replicative immortality –> ability to replicate indefinitely –> alterations in mitochondria metabolic pathways
What nutrients can be used to generate ATP?
lipids, cell membranes
sugars, DNA, proteins, cell membranes
proteins, DNA
What is the Warburg effect?
describes an increased lactate production by cells under aerobic conditions
What are the 2 common misunderstandings of the Warburg effect?
- Warburg Effect can never be observed in hypoxia
2. It does not necessarily describe increased aerobic glycolysis which is not unique to cancer cells
So why is the Warburg Effect always talked about?
- we observed increased lactate production in cancer cells and in most tumours
- it is an indicator of metabolic transformation of tumour cells, but there are a number of different ways of getting this effects
How does the Warburg Effect, and other transformed metabolic phenotypes occur?
What are the 4 examples covered in this lecture?
Oncogene/tumour supressor gene induced changes in proliferative drive, and direct modulation of metabolism Examples covered: - PTEN - TP53 - K-Ras - c-Myc
How is PTEN involved in cellular energetics?
- mutant PTEN does not dephosphorylates PIP3 to PIP2
- This increases Akt
- Akt is responsible for translocating GLUT4 transporters onto the cell membrane
- This increases glucose uptake as transport is diffusion limited
- This increases glycolysis
How is p53 involved in cellular energetics?
- central metabolism regulator
- it increases transcription of hexokinase and TIGAR which increases rate of glycolysis
- it controls oxidative phosphorylation through SCO2
- SCO2 is part of the inner mitochondrial membrane an required for Cytochrome complex 4 production, forms part of the electron transport chain.
- p53 deficient tumours therefore exhibit the Warburg Effect
What happens if TP53 is mutated instead of knocked out?
Retention of its ability to upregulate enzymes involved in:
- detox oxidative stress
- DNA/RNA synthesis
- oxidative ATP generation
- increased glucose consumption
How is c-myc involved in cellular energetics?
- c-myc transforms glutamine metabolism
- c-myc amplification often observed in tumours
- c-myc upregulates glutamine transporters and glucose transporters
- this is good because you can synthesise a lot from glutamine
- c-myc allows the generation of materials needed for anabolism
How do PTEN and c-myc work together?
PTEN drives glycolysis
c-myc drives OP, via TCA cycle
- using different nutrients in from different sides
—> proliferation
What is the role of k-ras mutations in cellular energetics?
- K-ras transforms the food source
- induces tumour cells to increase uptake of external protein
- can use this to directly generate new proteins, ATP and DNA/RNA
- works well if tumour is starved of glucose and oxygen
What familial cancer syndromes illustrate the role of metabolism in cancer?
- succicinate dehydrogenase deficient in paragangliomana and phaeochromocytoma
- fumarate hydrates deficient in leiomyoma and renal cell carcinoma
= succinate and fumarate levels increases and disrupt normal cell signalling processes as their effect on ak-glutatrate dependent dioxygenases is stopped –> akglutate used in AA metabolism
