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BIOL3043 - Cellular and molecular pathology > Lectures 13 & 14 - Cell metabolism and cancer > Flashcards

Lectures 13 & 14 - Cell metabolism and cancer Flashcards

1
Q

Explain the hypothesis for the origins of cancer

A

Boveri, T. “Concerning the origins of malignant tumours” [in german] (1914). English translation (2008)

Warburg, O. “On metabolism of tumours” [in german] (1924) Reviewed by Warburg in english (1956)

Tumour viruses carry oncogenic genes. Cellular oncogenes and tumour suppressor genes (TSGs) cause cancer.

Mutations in mitochondrial genes (genes encoded by nucleus but then used in Mt) cause (rare) cancers. Mutated oncogenes and TSGs cause “The Warburg Effect”

Both agreed that:
1. DNA mutations alter metabolism
2. Metabolism alters gene expression

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2
Q

What is one of the emerging hallmarks of cancer

A

Deregulating cellular energetics

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3
Q

Explain glucose metabolism in mammalian cells

A

Blood vessel along the top supplying oxygen, needed to drive the electron transport cell

Glucose goes through the glycolytic pathway, kicks out a little bit of ATP, makes pyruvate which goes into the mitochondria

TCA cycle creates things which go into the ETC, which pumps electrons across membrane to create lots of ATP

Sometimes pyruvate is converted into lactate (usually when lack of oxygen due to no oxygen to run ETC)

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4
Q

Describe imaging that can be done on patients with lymphoma to show spread of cancer

A

Positron-emission tomography imaging with 18 fluoro-deoxyglucose [FDG-PET]

Parts of body with high glucose uptake will show up, this includes cancer, but will also show at bladder and brain irregardless of cancer presence or not (heart shows up but if you take image as its contracted, it doesn’t)

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5
Q

Explain imaging with 18FDG-PET in breast cancer subtypes

A

Quantified and given a number as tohow bright it us

In the different subtypes of breast cancer yo get a more differentiated and more aggressive cancer cell type, the more aggressive the cancer the more glucose metabolism will be occurring and therefore more will show on scans

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6
Q

Tumours are oxygen deprived due to what?

A

Poor vasculature

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7
Q

What are the different parts of a late stage ductal carcinoma

A

Necrotic core
Tumour
Stroma
blood vessels

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8
Q

What does imaging of necrosis tell you about the vasculature of a tumour

A

It shows you how far the oxygen can get

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9
Q

Describe the hypothesis of Hypoxia mediated selection

A

Increased aerobic glycolysis makes the tumour cell more able to survive periods of low oxygen availability

Warburg 1956

Gatenby & Gilles 2004

Hypoxia-mediated selection of cells with diminished apoptotic potential to solid tumours

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10
Q

What about warburgs theorys were not correct

A

He thought of everything had to be defined in terms of metabolism, which is not totally correct

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11
Q

Whats the rate limiting enzyme in glycolysis

A

PFK1:
Inhibited by ATP
Activated by AMP

so when oxygen gets used up theres more AMO so becomes active

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12
Q

What are HIFs?

A

Hypoxia inducible factors, important hallmark of cancer

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13
Q

How is HIF regulated

A

Rapidly degraded by a ubiquitinligase by modification to one of the hydroxyl groups on one of the proline residues on HIF

Tag proline of HIF protein and a big ligase come to degrade

take away oxygen, Doesnt get tagged and degraded, so levels increase

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14
Q

explain what happens when HIf1a is not degraded?

A

When theres lack of O2, its not degraded

Binds to promoters and activates many things that lead to increase of glucose metabolism

reversible though

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15
Q

What leads to irreversible regulation of glycolysis

A

mutations in fumarate hydratase (FH) and succinate dehydrogenase (SDH)

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16
Q

What type of cancers are FH and SDH mutations mostly seen in

A

familial cancers, particularly renal tumours

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17
Q

What occurs in tumours found with mutations in FH and SDH?

A

Mitochondrial ATP synthesis is impaired

The substrates of the enzymes encoded by FH and SDH (fumarate and succinate) accumulate

Fumarate and succinate inactivate PHDs, causing increased HIF1α

HIF1α increases glycolysis and other hallmarks of cancer

“ONCOMETABOLITES” - small molecules/metabolits that feed into gene regulation, causing or contributing to cancer

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18
Q

What does the protein VHL do?

A

TSG
targets HIF1a for degradation
Mutations are associated with renal cancers

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19
Q

Explain hypoxia and pseudo-hypoxia

A

Under hypoxic conditions HIF1α is activated, promoting glycolysis and well as other hallmarks of cancer (angiogenesis & migration).

Mutations in tumours (FH, SDH, VHL, IDH1) cause irreversible “pseudohypoxia” to promote glycolysis & tumorigenesis

One hypothesis is that this enables cancer cells to better tolerate periods of hypoxia

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20
Q

What are the two different theories of glycolysis in cancer?

A

1st : Oxygen shortage
2nd: Glycolysis fulfils metabolic requirements for cancer

21
Q

What is proliferation controlled by in unicellular organisms?

A

Nutrients - in absence of nutrients, go into starvation mode

22
Q

What is proliferation controlled by in multicellular organisms?

A

growth signals:

no growth signal – cell uses mostly sugar to produce ATP - don’t do excessive amounts of glycolysis

With Growth signal:
use glucose to make ATP but also more biomass

e.g. of growth signal would be a T memory cell needing to respond to immune response

23
Q

What are the different types of metabolism

A

aerobic and anaerobic respiration

24
Q

Under hypoxia, what process is needed to regenerate NADH

A

lactate generation (anaerobic glycolysis)

25
Q

Describe the different things that glucose is used for in the cell

A

10% - diverted to biosynthetic pathways upstream of pyruvate
5% goes to mitochondria
85% goes to lactate

26
Q

What are the benefits of glycolysis to a proliferating cell?

A

fast, allowing rapid proliferation.

The waste product (lactate) is recycled to glucose by the liver (Cori cycle) (so is not wasted)

27
Q

What does growth factors feeding into kinases increase?

A

Glycolysis

28
Q

What does the pentose phosphate shunt do?

A

-Actvated by p53

-Generates NADH - providing reducing power to the cell to regulate TCA cycle (protecting mechanism)

-generating ribose sugars - building block for DNA

29
Q

Describe what happens at the decision point of pyruvate going into the mitochondria

A

Pyruvate kinase M2 (PKM2) is blocked out, as other models suggest it diverts pyruvate to lactate

30
Q

What is the known role of AMPK

A

promoting glycolysis, although AMPK appears to be blocked out in the model, review by Hardie says it activates the PFK step

31
Q

Explain what happens in metabolism if 39 glucose enter

A

6 go onto pentose phosphate pathway, but some of these come back
36 continue
1 to serine pathway
1 to alanine synthesis
74 lactate come out (think it would be 72, but more due to glutamine)

32
Q

Explain how mitochondria generate harmfull reactive oxygen species (ROS)

A

Pyruvate enters the mitochondria as Acetyl-CoA

This enters the TCA cycle where electrons (energy) are donated to NAD+ and FAD to generate NADH and FADH2

Electrons from NADH and FADH2 are passed through the electron transport chain to generate the mitochondrial membrane proton

Respiratory complexes leak electrons to oxygen to produce superoxide O2-

These can lead to damage to nucleic acids, lipids and proteins.

O2- production increases when ETC activity is > ATP demand

33
Q

What is required to neutralise the ROS in mitochondria?

A

NADPH from the pentose phosphate pathway

34
Q

What is the pentose phosphate pathway needed for?

A

DNA and RNA synthesis
NADPH needed to neutralise ROS made from ETC

35
Q

What is common in most normal tissues PKM1 or PKM2

A

PKM1

36
Q

Explain features of PKM1

A

PKM1 is the enzyme most common in normal tissues. It is :

-active

-channels its product (pyruvate) to the mitochondrial enzyme pyruvate dehydrogenase

37
Q

Explain features of PKM2

A

PKM2 prevalent in cancer cells. It is:

-less active than PKM1

-regulatable

-channels pyruvate to the cytosolic enzyme lactate dehydrogenase

38
Q

How does PKM2 limit ROS production and increase nucleotide synthesis?

A

Restricts pyruvate entry into the mitochondria, and increase concentration of glycolytic intermediates to fuel Pentose phosphate pathway (and serine biosynthesis as also needed for DNA/RNA)

so ROS protection and nucleotide synthesis

39
Q

What is PKM2 expression regulated by?

A

Alternative mRNA splicing

40
Q

What oncogne promotes PKM2 expression in cancers?

A

c-mcy - promotes expression of splicing factors which promote PKM2 expression

41
Q

What does mcy drive

A

Glucose and glutamine metabolism

42
Q

How does p53 Promote the PPP

A

By suppressing glycolysis, p53 also promotes mitochondrial respiration

43
Q

Explain how metabolism is cell cycle regulated

A

PFKFB3 is an (indirect) activator of PFK1.

PFKFB3 is targeted for destruction by APC/Cdh1

Cdh1 is targeted for destruction by G1/S cyclin/cdks

Hence G1/S cyclin/cdks promote glycolysis

Glycolysis is required for S phase entry

44
Q

What did Otto Warburg in the 1920’s first note about tumours

A

Metabolic change between tumours and normal tissues

45
Q

Cancer associated changes in metabolism can be caused by mutations in what?

A

Oncogenes and TSGs

46
Q

What are the consequences of metabolic changes in cancer cells?

A

Increased glycolysis

Reduced reliance on oxygen for ATP generation

Increased protection from reactive oxygen species (ROS)

Increased supply of metabolites to anabolic pathways

e.g DNA and protein synthesis

47
Q

Explain how imaging glucose uptake shows if cancer treatment is effective

A

[18F]-FDG-PET imaging is used for clinical management of cancer patients for many tumour types

Looked at glucose uptake before and after drug treatment – reduction in. Glucose uptake means drug worked, either the cells have become less glycolytic, or there are less cells there to uptake glucose

48
Q

Explain some therapies in development and trials for treatment of cancer through affecting metabolism

A
  • 2-deoxyglucose (2-DG) - Blocks glucose uptake by inhibiting HK2. In clinical trials

-Lactate dehydrogenase A inhibitors - Lead compounds work in mouse models, by inducing ROS – no drugs yet

-MCT4 inhibitors - block lactate export. Compounds in development

-Dichloroacetate - Blocks PDK1 resulting in pyruvate flux into the mitochondria, and thus ROS. Clinical trials

-Metformin; an anti-diabetic drug that inhibits complex I in the mitochondria and results in AMPK activation - Observation from diabetic patients have lead to clinical trials for cancer

49
Q

Do cancer cells stay alive with less or more energy than they need for growth

A

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BIOL3043 - Cellular and molecular pathology (11 decks)

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