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Cancer mechanisms and therapeutics > Cancer metabolism > Flashcards

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
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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
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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
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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
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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
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6
Q

What are the key things required to support chronic inflammation of cancer cells?

A

energy and biosynthetic intermediates

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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
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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
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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
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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
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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
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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
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13
Q

What can drive the Warburg effect? (3)

A
  • mutations in oncogenes and TSGs
  • changes in growth factor signalling
  • Hif1a
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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
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15
Q

What is Hif1a?

A
  • hypoxia inducible factor 1 alpha
  • major driver of the Warburg effect
  • oncogenic regulator
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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
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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
Q

What kinds of biosynthesis products from the TCA cycle are important for cancer cells

A
  • 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
Q

Can glutaminolysis (glutamine to glutamate to A-KG) be targeted in cancer?

A
  • 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
Q

What kinds of enzymes might be mutated to change cancer cell metabolism and be transforming?

A
  • TCA cycle enzymes
  • IDH (somatic)
  • SDH and FH (heritable -> cancer predisposition)
28
Q

What is the role of IDH in the TCA cycle?

A

citrate into a-KG

29
Q

What is the role of SDH in the TCA cycle?

A

succinate - fumerate

30
Q

What is the role of FH in the TCA cycle?

A

fumerate - malate

31
Q

How can FH and SDH be mutated in cancer?

A

inheritence of 1 defective copy of FH or SDH leads to aggressive cancer - result n the same downstream affects if either are mutated

32
Q

What happens when FH or SDH are lost?

A
  • 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
Q

What mutations of IDH 1+2 can be seen in cancer?

A
  • 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
Q

What happens when D2HG accumulates int the cell?

A
  • similar to SDH and FH
  • hypermethylation of histones and DNA
  • adding D2HG to cells is enough to transform them into cancer phenotypes
35
Q

What are oncometabolites?

A
  • metabolites that once they accumulate to high levels can act to cause cancer
  • succinate, fumerate, D2HG
36
Q

Can mutant IDH 1+2 be targeted in therapy? What are the 2 problems?

A
  • 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
Q

How does aspirin affect coloreactal cancer?

A
  • reduces the risk and progression
  • may affect metabolic reprogramming
38
Q

What initially suggested that Asprin may alter metabolic processes in colon cancer?

A
  • cultured cells in asprin for a year
  • many proteins were upregulated and downregulated as a result
  • many of these were involved in metabolism
39
Q

In what way does Apsrin alter metabolism?

A
  • 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
Q

How does Asprin affect the carbon SOURCES used in the TCA cycle?

A
  • increases glucose incorporation
  • decreases glutamine incorporation
41
Q

How could the effects of Asprin be used to kill cancer cells?

A
  • 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

Cancer mechanisms and therapeutics (12 decks)

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