Molecular regulation of health and disease (HAP31806)
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Lecture Notes Molecular Regulation of Health and Disease, HAP31806
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Molecular regulation of health and disease (HAP31806)
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Wageningen University (WUR)
Lecture Notes Molecular Regulation of Health and Disease, HAP31806. Course is given in the first year of the MSc Biotechology at Wageningen University.
Molecular regulation of health and disease (HAP31806)
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Lecture notes molecular
regulation of health and disease
Introduction theme 1
1. Sustaining growth
signalling can be
achieved due to
abnormal receptors that
are GFreceptors produce
their own activation
signals and can thereby
activate downstream
signalling pathways
without the need of a
ligand.
2. Tumour cells can escape
programmed cell death
and can survive even when they are damaged. Thus, the cell death programs are altered in
cancer cells.
3. Normally, tumour suppressor cells (p53, Rb) block cell proliferation in case of cell damage ,
but these cells are mutated when cancer occurs. Now, proliferation is not blocked anymore.
4. Also, telomeres are altered, resulting in a continued replication and immortal cells in culture.
5. Cancer cells can induce angiogenesis, where blood vessel formation is activated. This could
cause the transfer of more nutrients to the tumour to promote growth. Immune cell
infiltration can promote angiogenesis.
6. Cells undergo epithelial to mesenchymal transition so they can spread to distant sites. This
process is known as metastasis (=invasion).
We need metabolism to produce energy and biomass. Energy occurs in the form of ATP and biomass
occurs in the form of proteins, DNA and cell membranes.
Cancer cell metabolism
Glycolysis: where glucose is converted into pyruvate. Pyruvate can
be converted to lactate (anaerobic), or it can be used in the
mitochondria for the TCA cycle (aerobic).
Fatty acids can also be nutrients for the TCA cycle. Fatty acids can be
oxidized in the mitochondria in the fatty acid oxidation cycle (FAO),
of which the products can be used in the TCA cycle. The result of the
TCA cycle is the production of ATP and NADH.
Glutamine can be converted to glutamate, and glutamate can also
enter the TCA cycle to produce ATP. Another role of glutamate is to
generate lipids. Lipids can be generated via the TCA cycle or via the
cytosol, and the lipids are used to make the cell membrane.
Intermediates of the conversion of glucose to pyruvate are precursors for DNA production. The
pentose phosphate pathway (PPP) produces the ribonucleotides used to built DNA, and PPP uses the
,metabolites from the glycolytic pathway.
The glycolytic pathway also results in building blocks for amino acids, and thus for proteins.
Glucose and glutamine use in cancer and normal cells
Otto Warburg: discovered a lot about the cancer metabolism, already in the 1920s. The Warburg
experiment involved addition of glucose to cancer cells to see if the cells would become acidic. If you
have cells, and you give them glucose, the pH of the culture medium goes down. Thus, the cells
become acidic. The tumour will use the glucose, but it needs oxygen to burn the glucose. If you trap
the carbon dioxide, you could analyse how much oxygen is used by the tumour, due to a pressure
decrease in the vessel. Warburg also wanted to measure the level of fermentation by determining the
amount of carbon dioxide. Carbon dioxide is the product of lactic acid conversion. In tumours,
Warburg discovered that there was a massive increase in carbon dioxide formation. So, tumours have
a high rate of lactic acid formation.
Pasteur effect: a high oxygen concentration inhibits glycolysis in yeast.
In tumours, even if there were high levels of oxygen, a lot of carbon dioxide formation was seen.
Thus, even with high levels of oxygen, a lot of lactic acid formation occurs. 10 times as much glucose
is consumed in fermentation compared to glucose consumed during respiration (in the presence of
oxygen).
Benefits of the Warburg effect in tumour cells:
Rapid ATP synthesis: Warburg effect increases access to a limited energy source (ATP). The
glycolytic rate is 100x times higher than the rate of glucose oxidation, meaning that you can
produce more ATP faster than in normal cells. For this rapid glycolysis, a lot of glucose is
necessary.
Biosynthesis: promotes flux into biosynthetic pathways.
Thus, increased glucose utilization is used as a carbon
source for anabolic processes needed to support cell
growth. The glycolytic pathway is needed to produce
ribonucleotides (using PPP) to produce DNA.
NADPH is also produce using the PPP. NADPH is needed
to produce glutathione, which is used for antioxidant
defence. NADPH is also used to produce lipids.
Tumour microenvironment: a high rate of glycolysis
enhances disruption of tissue architecture and immune cell evasion. Lactic acid formation
makes the surroundings of the cell more acidic, to promote invasiveness. This acidity also
takes away the glucose from other, native immune cells.
Cell signalling: allows for signal transduction through
ROS and/or chromatin modulation. Chromatin is the
combination of DNA and histones in the nucleus.
Histones are acetylated to open the DNA. In the case of
acetylation, active transcription can occur. For this,
acetyl-CoA is needed, coming from glycolytic
conversion.
Glutamine: an amino acid
essential for cancer cell growth.
Glutaminolysis is the
breakdown of glutamine to
, pyruvate or lactate. Glutamine is converted in the mitochondria, whereas glycolysis occurs in the
cytosol. Glutamine is used for lipid synthesis, for making nucleoids, and to obtain NADPH.
Lipogenesis occurs in the cytosol by converting citrate into lipids.
Using reductive carboxylation, glutamate can also be directly converted to alpha-KG, which can be
further converted to isocitrate. Isocitrate can be converted to citrate, after which lipogenesis in the
cytosol can occur. Reductive carboxylation was discovered using metabolic labelling studies (with
heavy isotopes). Mass spectrometry could be further used to track the metabolites. In the image: the
red star indicates the labelling.
Alternative fuels for cell function and survival
Cancer cells need to adapt to different metabolic environments, for example low glucose conditions
or hypoxic conditions. Cancer cells are flexible in using different types of metabolites to deal with
fluctuating situations.
Autophagy is one of the breakdown pathways. Breakdown is very specific: proteins can be tagged
with an ubiquitin molecule to be broken down by a
proteasome. It can also be less specific using endocytosis,
where molecules are transported into a lysosome to be
broken down. In autophagy, parts of the cell are broken down
into vacuoles. These vacuoles fuse with the lysosome to break
down the constituents.
Autophagy can be non-selective, where cytosolic proteins and
organelles are broken down. If autophagy is selective,
organelles are tagged for degradation.
Autophagy is a process for removal of damaged parts and
recycling building blocks. Autophagy is a pro-survival process, but continued autophagy leads to cell
death. Autophagy related gene proteins (Atg proteins) regulate autophagy.
Process of autophagy:
1. ULK1 complex formation occurs (Atg1)
2. Lipid membranes of the cell are extracted
3. Beclin-1 complex formation
4. Indicates the initiation of phagophore formation
5. Recruitment of Atg5, Atg12, Atg16, and LC3
6. Membrane elongation to produce a coating membrane
7. The autophagosome can fuse with the lysosome to form
an autolysosome
8. Macromolecules are broken down
9. Smaller constituents are released to be recycled
Cancer stem cells are quiescent cells that are resistant to therapy. They have low metabolic rates and
are set to survive instead of proliferation. Cancer
stem cells can renew the cancer cell pool. Cancer
stem cells need different fuels than normal cancer
cells (see image).
Fatty acid oxidation starts with palmitate. The fatty
acid oxidation takes place in the mitochondria.
The enzyme CPT1, carnitine palmitoyl-transferase
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