Cancer metabolism Flashcards
What is cancer metabolism?
- the metabolic processes which occur in cancer cells that drive or contribute to the malignant phenotype
- usually the same pathways as in normal cells
- provide a growth/survival advantage
How and why do cells need to meet the metabolic challenges of proliferation?
- proliferation is demanding - need to double their mass every time
- take up more nutrients
- adapt to metabolic stress
- undergo metabolic reprogramming
What are the main carbon sources for both normal and tumour cells?
- glucouse and glutamine
- can use others
- lactate used to be thought to be a waste product but can actually be used as an energy source too
What do cancer cells use as their carbon sources?
- glucose and glutamine contribute significantly to cancer cell biomass
- can take in many others such as amino acids, fatty acits, lactatae
- can even break down whole proteins for use as energy
- not picky with their energy source
How do cancer cells or other growing cells adapt to metabolic stress?
- will reach a point where cells in the middle are undergoing hypoxia or not enough nutrients
- continues until angiogenesis occurs
- process can be uneven in cancer with some parts of the tumour not getting relieved from their metabolic stress
What are the key things required to support chronic inflammation of cancer cells?
energy and biosynthetic intermediates
What happens to cancer cell metabolism as they’re transformed into cancer cells?
- metabolic reprogramming
- activated by oncogenes such as myc and PI3K
- or by TSG losses like p53 and PTEN
What are the important points of glycolysis and the TCA cycle?
- Glucose - pyruvate - AcCoA is glycolysis and supplies carbons to the TCA cycle (provides 2ATP)
- the TCA cycle makes 36 ATP
- can also be supplied by glutamine - glutamate - AKG
What is the Warburg effect?
- cancer cells use glycolysis for energy production even with ample oxygen for teh TCA cycle and ETC
- dont use their mitochondria
- coined aerobic glyclosys and is also used by normal proliferating cells
- marked by high gluclose consumption and lactate production
What is the process of aerobic glycolysis in the Warburg effect?
- gluclose converted into pyruvate
- 5% of it enters the mitochondria for oxidative phosphorylation
- 95% is converted into lactate
- very inefficient - provudes 4 ATP let mol of gluclose rather than the usual 36
Why do proliferating and cancer cells switch to such an inefficient form of metabolism?
- focus is on production of biosynthetic intermediates
- amino acids, nucleic acids, fatty acids etc
- while still forming some ATP
Is lactate a waste product?
- normal and expecially tumour cells can take lactate and convert it back into pyruvate to re-enter the TCA cycle
- can prioritise making biosynthetic intermediates from glucose and carbon while using lactate to keep the TCA cycle running by aerobic glyclosys
What can drive the Warburg effect? (3)
- mutations in oncogenes and TSGs
- changes in growth factor signalling
- Hif1a
How is growth factor signalling altered in cancer cells to drive the Warburg effect?
- normally pathways are only activated when cells require glucose
- mutations in growth factor receptors can lead to excessive glucose uptake that drives the Warburg effect
What is Hif1a?
- hypoxia inducible factor 1 alpha
- major driver of the Warburg effect
- oncogenic regulator
How is Hif1a regulated in normal cells?
- regulated by oxygen content
- hydroxylated and bound to BHL for degradation when oxygen levels are high
- when oxygen is low it stops getting degraded
- binds Hif1B which binds responsive elements and transcribes glycolysis gebes such as LDH, pyruvate kinase and HK2
How is Hif1a deregulateed in cancer?
- kept active even in the presence of O2
- for example by the loss of Hif1B
What is pyruvate kinase?
- key enzyme in glyclosis and the Warburg effect involved in O2 to pyruvate
- 2 isoforms M1 and M2
- PK-M2 is expressed more in cancer cell lines and primary tumours
- switch from M1 to M2 can be transformational M2 can enhance tumour progression
How does the M2 isoform of pyruvate kinase enhance tumour progression?
- M2 less active than M1
- slows down the last step of glycolysis
- allows biosynthetic intermediates to build up
How can the Warburg effect be exploited for cancer imaging?
- PET scan
- hih rates of glucose metabolism
- can use radiolabelled glucose that is able to begin glycolysis byut not complete it allowing it to be detected
- not appropriate for brain tumours as the brain has so much glucose uptake the difference cant be seen
How can the Warburg effect be targeted for cancer therapy?
- 2DG
- gets converted by hexokinase part way through glycolysis but cant continue so cells die
- but toxic to patients clinically
- drugs to inhibit hexokinase show some promise along with chemo but are also toxic and only a last resort
How can the high levels of lactate in cancer cells be targeted?
- drigs targeting the transporter by which lactate leaves the cell
- builds up and becomes toxic
- slightly specific to cancer cells as WT cells have less lactate to build up
- also prevents cancer cells from taking lactate back in as a fuel source
What happens when components of the electron transport chain are removed in cancer cells?
- suppresses cell growth
- shows that cancer cells don’t prioritise the Warburg effect at the expense of oxidative metabolism
- mitochondrial respiration is still required for survival
Which carbon source is important in cancer + proliferating cells?
- glutamine supports proliferation by replenishing depleted TCA cycle intermediates
- also important in biosynthesis and provides nitrogen for nucleotide and amino acid biosynthesis
What kinds of biosynthesis products from the TCA cycle are important for cancer cells
- fatty acits - form cell membranes so important for proliferation
- amino acids - OAA -> aspartate, glutamate into proline etc - building blocks of proteins
- amino acids are also involved in cancer signalling pathways
Can glutaminolysis (glutamine to glutamate to A-KG) be targeted in cancer?
- cancer cells high dependence on glutamate makes it an attractive target
- drugs inhibiting glutaminase enzyme in phase II clinical trials
- not the only enzyme that does glutaminolysis so would only slow it down
What kinds of enzymes might be mutated to change cancer cell metabolism and be transforming?
- TCA cycle enzymes
- IDH (somatic)
- SDH and FH (heritable -> cancer predisposition)
What is the role of IDH in the TCA cycle?
citrate into a-KG
What is the role of SDH in the TCA cycle?
succinate - fumerate
What is the role of FH in the TCA cycle?
fumerate - malate
How can FH and SDH be mutated in cancer?
inheritence of 1 defective copy of FH or SDH leads to aggressive cancer - result n the same downstream affects if either are mutated
What happens when FH or SDH are lost?
- accumulation of succinate or fumarate
- inhibits some aKG-dependent dioxygenases important in DNA methylation
- leads to hypermethylation of DNA and histones and altered gene expression
- also stabilises Hif1a even in the presence of O2 leading to Warburg effect
What mutations of IDH 1+2 can be seen in cancer?
- acts as an oncogene
- AML, glioblastoma and more
- alters normal function and confers new enzymatic activity leading to further conversion of A-KG into D2HG
What happens when D2HG accumulates int the cell?
- similar to SDH and FH
- hypermethylation of histones and DNA
- adding D2HG to cells is enough to transform them into cancer phenotypes
What are oncometabolites?
- metabolites that once they accumulate to high levels can act to cause cancer
- succinate, fumerate, D2HG
Can mutant IDH 1+2 be targeted in therapy? What are the 2 problems?
- drugs in trials that target only the mutant form of the enzyme
- but not always effective
- IDH mutations occur early and treatment cant undo epigenetic changes already made
- as tumours accumulate mutations they become less dependent on mutant IDH
How does aspirin affect coloreactal cancer?
- reduces the risk and progression
- may affect metabolic reprogramming
What initially suggested that Asprin may alter metabolic processes in colon cancer?
- cultured cells in asprin for a year
- many proteins were upregulated and downregulated as a result
- many of these were involved in metabolism
In what way does Apsrin alter metabolism?
- downregulates PDK1 which is an inhibitor of PDH
- increases carbon entry into the TCA cycle
- increases carbon flow and pushes carbon into the TCA cycle
How does Asprin affect the carbon SOURCES used in the TCA cycle?
- increases glucose incorporation
- decreases glutamine incorporation
How could the effects of Asprin be used to kill cancer cells?
- because glutaminolysis is impared with asprin, the cells produce more glutaminase to try and compensate
- glutaminase inhibitors shut this off
- combination of inhibitors and asprin kills cancer cells and reduces colorectal cancer cell growth in mice
