Cancer metabolism Flashcards
1
Q
What is cancer metabolism?
A
- 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
2
Q
How and why do cells need to meet the metabolic challenges of proliferation?
A
- proliferation is demanding - need to double their mass every time
- take up more nutrients
- adapt to metabolic stress
- undergo metabolic reprogramming
3
Q
What are the main carbon sources for both normal and tumour cells?
A
- 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
4
Q
What do cancer cells use as their carbon sources?
A
- 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
5
Q
How do cancer cells or other growing cells adapt to metabolic stress?
A
- 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
6
Q
What are the key things required to support chronic inflammation of cancer cells?
A
energy and biosynthetic intermediates
7
Q
What happens to cancer cell metabolism as they’re transformed into cancer cells?
A
- metabolic reprogramming
- activated by oncogenes such as myc and PI3K
- or by TSG losses like p53 and PTEN
8
Q
What are the important points of glycolysis and the TCA cycle?
A
- 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
9
Q
What is the Warburg effect?
A
- 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
10
Q
What is the process of aerobic glycolysis in the Warburg effect?
A
- 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
11
Q
Why do proliferating and cancer cells switch to such an inefficient form of metabolism?
A
- focus is on production of biosynthetic intermediates
- amino acids, nucleic acids, fatty acids etc
- while still forming some ATP
12
Q
Is lactate a waste product?
A
- 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
13
Q
What can drive the Warburg effect? (3)
A
- mutations in oncogenes and TSGs
- changes in growth factor signalling
- Hif1a
14
Q
How is growth factor signalling altered in cancer cells to drive the Warburg effect?
A
- 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
15
Q
What is Hif1a?
A
- hypoxia inducible factor 1 alpha
- major driver of the Warburg effect
- oncogenic regulator
16
Q
How is Hif1a regulated in normal cells?
A
- 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
17
Q
How is Hif1a deregulateed in cancer?
A
- kept active even in the presence of O2
- for example by the loss of Hif1B
18
Q
What is pyruvate kinase?
A
- 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
19
Q
How does the M2 isoform of pyruvate kinase enhance tumour progression?
A
- M2 less active than M1
- slows down the last step of glycolysis
- allows biosynthetic intermediates to build up
20
Q
How can the Warburg effect be exploited for cancer imaging?
A
- 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
21
Q
How can the Warburg effect be targeted for cancer therapy?
A
- 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
22
Q
How can the high levels of lactate in cancer cells be targeted?
A
- 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
23
Q
What happens when components of the electron transport chain are removed in cancer cells?
A
- 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
24
Q
Which carbon source is important in cancer + proliferating cells?
A
- glutamine supports proliferation by replenishing depleted TCA cycle intermediates
- also important in biosynthesis and provides nitrogen for nucleotide and amino acid biosynthesis
25
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
26
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
27
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)
28
What is the role of IDH in the TCA cycle?
citrate into a-KG
29
What is the role of SDH in the TCA cycle?
succinate - fumerate
30
What is the role of FH in the TCA cycle?
fumerate - malate
31
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
32
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
33
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
34
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
35
What are oncometabolites?
- metabolites that once they accumulate to high levels can act to cause cancer
- succinate, fumerate, D2HG
36
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
37
How does aspirin affect coloreactal cancer?
- reduces the risk and progression
- may affect metabolic reprogramming
38
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
39
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
40
How does Asprin affect the carbon SOURCES used in the TCA cycle?
- increases glucose incorporation
- decreases glutamine incorporation
41
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
