Metabolism in cancer Flashcards
Why do cancer cells reprogram their metabolism?
It is necessary for the inappropriate growth in cancer.
What is the Warburg effect?
Otto Warburg first discovered the phenomenon of aerobic glycolysis in 1924 when he observed that cancer cells preferentially carried out the metabolism of glucose to lactate even under normal oxygen levels. While this isn’t a rule for all cancerous cells, it it is the best-known metabolic hallmark.
Why do cells prefer aerobic glycolysis even though it’s energy-inefficient?
- Glycolysis to lactate is energetically inefficient compared to the mitochondrial oxidation of pyruvate.
- Glycolysis is an anerobic reaction (it doesn’t require oxygen) – it converts glucose into pyruvate, which later can be converted into lactate.
- It only generates 2 ATP molecules per glucose. What is behind this?
I. Carbon intermediates can be used for anabolism of macromolecules – they can be directed to the PPP. The metabolism of cancer cells needs to be adapted to incorporate nutrients to produce a new cell.
II. They need to tolerate hostile conditions —> hypoxia, low nutrients and oxidative stress. Glycolytic intermediates can be used to generate reducing agents such as NADPH which are important in protection against oxidative stress.
III. Exporting excess acid (lactate) is needed for cells to survive the increase in glycolysis and this adaptation will give an advantage to the tumour cells, which will make invasion and metastasis of normal cells (which will suffer under acidic conditions) much easier.
IV. The metabolic signals can promote growth and survival in the tumour cells. Tumour cells have been shown to hijack metabolic machinery to signal the cells to continue growth.
What other metabolic changes are observed in cancer?
- Increased glycolysis and lactate production
- Increased glutamine uptake and metabolism
- Increased acid production and increase in export for cells to survive
- Increased lipid synthesis
- Increased nucleotide synthesis and folate dependency
These are all seen in rapidly dividing cells.
How does p53 regulate glycolysis and promote respiration?
- P53 is a key negative regulator of glycolysis.
- P53 is responsible for transcription of the metabolic TIGAR enzyme which reduces the levels of Fructose 2,6 BP which is an activator of PFK enzyme which acts on the glycolytic pathway.
- -Therefore in effect it was supressing the flow of carbon in glycolysis.
- P53 was also found to promote respiration by controlling transcription of a gene SCO2 which is needed for assembly of the oxidative phosphorylation chain in mitochondria.
- It also inhibits expression of the GLUT1 and lactate carrier MCT1 – a key point is that tumour cells consist of both aerobic and anaerobic cells –> the lactate exported from anaerobic cells can travel to be taken up by aerobic tumour cells by MCT1.
- In cancer, P53 is lost and therefore glycolysis is not supressed and respiration is not activated.
- This is a general pattern – oncogenes do the reverse by promoting glycolysis and inhibiting respiration.
Explain the role of the pyruvate kinase isoform in carcinogenesis.
- Pyruvate kinase is a multimeric protein (normally a tetramer) which converts PEP to pyruvate and thus generating an ATP molecule.
- In tumours, the PKM2 isoform is expressed which prefers to be in a dimer or monomer form and has a much lower affinity for its substrate PEP.
- In addition, various oncoproteins will help stabilise PKM2. There are also other de-activating mutations on the normal pyruvate kinase in cancer.
- The increase in glycolysis but decrease in its last step will cause accumulation of its substrate PEP, which can be used in anabolism. So glycolysis can be used for anabolism instead of just ATP generation.
- PKM2 has been found to interact with HIF as well as promote cyclin D and c-myc expression – acts as transcriptional co-activator.
- Levels of PKM2 have been correlated with the prognosis of glioblastomas.
Explain the role of glutamine uptake and reductive carboxylation in carcinogenesis.
- There is much higher glutamine uptake in cancer – important in amino acid synthesis.
- Also important to replenish TCA cycle intermediates –> glutamine can be converted to glutamate and enter the TCA cycle.
- A lot of TCA cycle intermediates are lost during rapid division especially citrate which is diverted for lipid synthesis.
- Anaplerosis is the name given to replenishing TCA cycle intermediates. This is regulated by c-myc, an oncogene.
- However, the TCA cycle is shut down in hypoxia so the cell has to perform reductive carboxylation (basically reverse of TCA cycle) so that glutamine can be converted to citrate therefore continue lipid synthesis
How are fumarate deydrogenase and succinate dehydrogenase seen as TSGs?
- Germ line mutations in FH and SDH enzymes in the TCA cycle can cause a particular spectrum of cancers due to the HIF-1 pathway.
- SDH catalyses conversion of succinate to fumarate while FH converts fumarate to malate.
- HIF-1 is an oxygen sensor and responsible for the hypoxia response. It’s tagged for degradation (via VHL) by hydroxylation on its proline residues by PHD enzyme and alpha KG as a cofactor.
- Mutations in SDH/FH causes a buildup of alpha-KG which in turn inactivates the degradation of HIF.
- -HIF is stabilised and can now transcribe genes for the hypoxia response —> glucose transport (increase GLUT1), angiogenesis and increase expression of the MCT4 transporter that exports lactate outside cells.
- Therefore FH/SDH are considered TSGs.
How is IDH considered an oncogene?
- Mutations in IDH are associated with gliomas and some leukemia.
- IDH enzyme converts isocitrate to alpha KG in the TCA cycle.
- Using metabolic profiling techniques, they found that oncogenic mutations (activating) would cause increase in the R132 mutant of IDH.
- It alters its function – R132 would convert the alpha-KG into 2-HG (instead of isocitrate) which is an oncometabolite.
- 2-HG can activate HIF pathway (and due to less alpha KG) and interfere with epigenetic regulation such as DNA methylation.
How is targeting the haem oxygenase enzyme a potential target for therapy?
- Mutation in FH (as a TSG) causes the accumulation of fumarate and succinate so the cell needs to get rid of these intermediates.
- They are shunted to haem metabolism pathways – haem is then converted to biliverden and hence bilirubin by haem-oxygenase enzyme.
- Because tumour cells are so dependent on this pathway to remove the accumulated intermediates, blocking the haem-oxygenase enzyme was found to selectively kill the tumour cells.
- Phenomenon known as selective lethality
