CBIO6: Cancer Metabolism Flashcards
Why do cancer cells become genetically reprogrammed to allow for improved cellular fitness?
1) To provide a selective advantage during tumourigenesis
2) To support cell survival under stressful conditions
3) To allow cells to grow and proliferate at pathologically elevated levels
What are the three main alterations that occur in cancer cells?
- Increased bioenergetics
- Increased biosynthesis
- Alteration in redox balance
When are the alterations in cancer cells important?
These 3 pathways are closely interlinked. Some activities become essential very early on in tumourigenesis as the primary tumour begins to experience nutrient limitations. Other changes occur later as cells undergo metastasis
What is the main energy source for most organisms?
Glucose
What is glycolysis?
The enzymatic process of breaking down glucose into pyruvate to extract ATP and NADH for cellular metabolism. Occurring mainly in cytoplasm.
Where does TCA/Krebs cycle occur?
Matrix of mitochondria
What happens in TCA cycle?
Set of chemical reactions used by aerobic organisms that completely oxidize the two carbon atoms of acetate (acetyl-CoA), into two molecules each of carbon dioxide and water with the release of stored energy in the form of ATP, NADH and FADH2 are also produced
What do glycolysis and the TCA cycle require?
Oxygen
Oxygen can range from _____ in the centre of solid tumours
0 – 2%
Why do cancer cells often exist in low nutrient low oxygen environments?
Tumours is that they grow very fast and rapidly outgrow the blood supply that feeds them
What is tumour hypoxia?
Occurs when cells are deprived of oxygen
Why would cancer cells become hypoxic?
They grow so fast that they out grow the developing blood supply
As the oxygen concentration decreases the further cells are away from blood vessels, what may happen to the centre of the tumour?
may become hypoxic and necrotic
What does the hypoxia Inducible Factor (HIF-1a) transcription factor in mammalian cells do?
It detects and monitors the levels of ambient oxygen
How does HIF-1 work?
HIF-1a stability, localisation, and activity are affected by oxygen levels. Under normal oxygen (normoxic) conditions, the HIF-1a protein is targeted for degradation. However, under low oxygen (hypoxia), HIF-1a protein degradation is prevented and levels accumulate. The HIF-1a transcription factor then binds DNA and activates hypoxia response genes
How many genes does HIF-1a activate? Give examples
60
VEGF and Erythropoiesis
What kind of genes does HIF-1a activate?
- increase angiogensis
- increase erythropoiesis
- increase cell survival
- glucose and iron metabolism
- Increased glucose flux
- Waste secretion
What does anaerobic respiration produce
Glucose -> lactate
Large amounts of ATP and NADH
Why do tumour cells ahve a lower extracellular metabolism?
Result of lactic acid export
Why is lower pH an advantage for tumour cells?
1) it can inhibit cytotoxic T lymphocytes which helps
tumour cells evade the immune system
2) helps activate enzymes required to digest local tissue for invasion
3) makes the local environment generally less favourable for normal cells
What is the normal and cancerous pH levels of cells?
Normal: 7.3-7.4
Cancer: 6.2-6.9
What else can drive forward glycolysis in cancer cells? Give two examples
Oncogene activation
- The activation of the oncogene Myc can upregulate genes involved in glucose uptake from the surroundings.
- The PI3kinase/Akt signalling axis can also stimulate glycolysis
What is the Warburg effect?
Where tumours take up large amounts of glucose compared to what was observed in the surrounding tissue. Additionally, the glucose is fermented to produce lactate. More importantly, it was discovered that tumours did this even in the presence of normal levels of oxygen.
What are the two major advantages of aerobic glycolysis in cells?
1) Cancer cells can live in conditions of varying oxygen levels (due to irregular functions of blood vessels) that would be harmful or lethal to normal cells that rely on oxidative phosphorylation to generate ATP .
2) Glycolysis generates rapid amounts of NADH and ATP – this is not as efficient as the TCA cycle - but is faster and better suits their rapid growth.
What is aerobic glyclysis also called?
The Warburg effect
Why would tumour cells break down so much glucose?
They need to obtain energy in the form of ATP & NADH - building blocks for biosynthesis
List the key generic types of biomolecules found in living cells?
DNA / RNA (nucleotides)
Proteins
Lipids
Carbohydrates
What are most biomolecules made from
hydrocarbons, carbohydrates, aldehydes and carboxylic acids.
Where do cancer cells siphon off carbon intermediates?
From glycolysis
What is NADH used for in the cell after aerobic glycolysis?
Used as a reducing agent in the anabolic reactions required for biosynthesis
What does the pentose phosphate pathway generate?
It generates ribose required for DNA and RNA synthesis as well as NADPH for further biosynthesis
What are the chemical changes made in the pentose phosphate pathway?
Glucose-6-phosphate is converted into Ribose-5-phosphate while generating CO2 and NADPH
What is hexosamine biosynthesis?
Where Modified carbohydrates glycosylate proteins to modify the functions and characteristics of the protein
What chemical changes occur in hexosamine biosynthesis?
1) Glucose-6-phosphate is converted into Glucose-N,6-phosphate by combining with glutamine
2) Glucose-N,6-phosphate is converted into acetylglucosamine, galactose, mannose, acetylneuraminic acid and fucose
What does glycolysation of proteins cause?
increase protein stability, solubility, and direct physical binding of cells to other cells
What happens in the glycerol-3-phosphate pathway?
Fatty acids are esterified with glycerol to form lipids
What is the first step of the glycerol-3-phosphate pathway?
Glucose is converted to glyceraldehyde-3-phosphate and dihydroxyacetone phosphate within the glycolysis pathway
Glyceraldehyde-3-phosphate is converted into what that is combined with fatty acids to produce lipids
glycerol-3-phosphate
How are fatty acids produced?
Using TCA cycle intermediates
Essential amino acids can be synthesised from ________
glycolysis intermediates.
Glucose is converted into ____________ which is combined with ______ to generate serine
3-phosphoglycerate
glutamine
Serine can be broken down to form _____ and other amino acids.
glycine
Glutamine is a major ______ donor for amino-acid synthesis, glucosamine synthesis, and purine and pyrimidine synthesis
nitrogen
What do cancer cells take up via SLC transporters?
Glutamine
What is the name of the transporters by which glutamine is uptaken into cancer cells?
SLC1A5 and SLC7A5
By what process can TCA intermediates be replenished by glutamine? What happens in this process?
Anaplerosis: allows citrate to be diverted for fatty acid synthesis.
What does the extra metabolism in cancer cells results in the production of?
reactive oxygen species such as:
O2-
H2O2
OH·
Where can ROS be generated? When does this occur?
Mitochondria when electron flux exceeds the capacity of ATP synthase. This requires cancer cells to upregulate ROS scavenging mechanisms and enzymes
How can glutathione scavenge ROS?
Becoming oxidised, aided by the enzyme glutathione peroxidase (with selenium)
If left in the cell how can ROS damage lipids?
By forming lipid hydroperoxides which can cause cell membrane perturbations and lead to cell rupture and cell death
If proteins are damaged by ROS what does this lead to?
Peroxidation of amino acid side chains or cross-linking of cysteine residues to form cystine
Free radicals can also cause what type of damage to DNA?
Damage to bases, mismatches and double-strand breaks
What can hydroxyl radicals oxidise guanine into? What does this lead to?
8-oxoguanine which erroneously pairs with adenine, increasing base mutations of DNA
What does growth factor stimulation lead to?
Activates anabolic downstream signalling which upregulates glycolytic flux and fatty acid synthesis
By what oncogenes is glycolytic flux and fatty acid synthesis upregulated
PI3K/Akt, Ras, Myc and Src
What does c-Myc do?
Increases glucose transporter and glycolytic enzyme expression, including that of splice variants of enzymes with increased glycolytic activities. c-Myc also inhibits HIF1a breakdown.
What activity activates tumour suppressor genes such as p53?
- Upregulation of oncogenic or stimulatory pathways
- Rapid ROS production,
- Activates tumour-suppressor genes
What genes can p53 activate?
- halt the cell cycle
- inhibit or reverse the glycolytic pathway
How do p53 genes inhibit or reverse the glycolytic pathway?
Specifically inhibit glucose transporter expression
What is TIGAR?
TP53 inducible glycolysis and apoptosis regulator gene
What is TIGAR induced by?
p53
What does TIGAR code for?
An enzyme which removes a phosphate from fructose-1,6-bisphosphate to reverse this key step in glycolysis
What can ROS produced during normal metabolism can be dealt with?
Anti-oxidant mechanisms within the cell
Elevated ROS levels can ….
damage cellular components which activates p53 which can halt the cell cycle, trigger apoptosis and inhibit glycolysis
Cancer-cell genomes show?
- Global hypomethylation
- Gene-promoter specific hypermethylation (tumour suppressors silenced)
Name a gene involved in the glycolysis and biosynthetic pathway that is upregulated in cancer cells
Transketolase
What causes the upregulation of transketolase?
Promoter-specific hypomethylation seen often in squamous cell carcinomas
What steps in glycolysis are downregulated in cancer cells and how is this done? How? To what effect?
Genes involved in governing the reversible steps of glycolysis (fructose-1,6-bisphosphate) are downregulated through hypermethylation, seen in gastric cancers, which increases glycolysis.
What does glucose influx cause an increase of?
Acetyl-CoA within the cell triggers Ras and Akt pathways which cause histone acetylation and a decrease of DNA condensation thus increasing gene activity
DNA methylation on CpG motifs occurs using what?
DMNT and SAM ( the universal methyl donor)
Where and can histones be methylated?
At arginine and lysine sites using HMT and SAM
What does one-carbon metabolism facilitate? What is this
the uptake of SAM and is determined by the cellular uptake and availability of methionine as well as the availability of serine and glycine
What are the chain of events caused by one-carbon metabolism?
- Oncogene activation increases glucose and glutamine uptake which increases glycolysis
- Biosynthesis of amino acids (including methionine) is increased
- Increased methionine allows for increasing gene methylation
- Tumour-suppressor genes and apoptotic genes may be silenced
- Increased cell survival and increased growth
What is imaging of cancer cells performed by?
Deoxyglucose
How does deoxyglucose show where cancer cells are?
It becomes trapped in the fast dividing cancer cells as it cannot undergo isomerism
How is deoxyglucose imaged?
It is radioactively tagged (fluoro-2-deoxyglucose), and can be imaged using scintillation counters in a ring using a PET scanner.
Summaries the Warburg effect
1) It is an adaptation to a low-oxygen environment.
2) It may be a consequence of genetic changes in cancer cells.
3) It is a rapid mechanism for energy production.
4) It may involve downregulation of mitochondrial activity in general (as they are involved in apoptosis – which cancer cells switch off).
5) It may involve the generation of glycolytic intermediates for biosynthesis.
