Molecular Regulation of Health and Disease - Detailed Summary
The summary contains important information from the lectures, reader (including images) and test exams.
Molecular Regulation of Health
and Disease – Lecture notes
Theme 1 – Molecular Regulation of Energy and Nutrient
Metabolism
Part 1 – Introduction/ cancer metabolism
Hallmarks of a cancer cell 2000:
Sustaining proliferative (growth) signalling
o Abnormal receptors (always activated)
o Production of own activation signals
Resisting cell death: tumour cells escape apoptosis
Evading growth suppressors: mutation in genes that supress tumour cell growth (P53, Rb= tumour
suppressor genes) growth suppression does not work.
Enabling replicative immortality: continued replication related to altered telomeres (enhanced telomerase
activity synthesis and extension of telomeres) Immortal cell culture
Inducing angiogenesis:
o angiogenesis is triggered by a lack of nutrients and causes blood vessel formation
Activating invasion and metastasis: A mass of tumour cells can enter the blood (Mesenchymal transition
state) and spread through organs.
,Part 2 – Warburg - Glucose and glutamine use in cancer and normal cells
The Warburg experiment indicates the of usage glucose by cancers cells by acidification of a glucose suspension
(lower pH indicates less glucose and more carbon dioxide in the solution). Respiration was measured by means of
pressure differences, a pressure decrease indicates oxygen consumption by the cancer tissue. Fermentation (lactic
acid production) was measured by checking CO2 production (lactic acid and bicarbonate react into CO2). A pressure
increase indicated fermentation. Warburg’s experiment indicated that tumours have a high lactic acid production.
Warburg also tested CO2 production under both aerobic and anaerobic conditions and was surprised that even under
aerobic conditions (O2 is present), tumours still produce lactic acid. The Warburg effect: even under aerobic
conditions, tumour cells will consume 10 times the amount of glucose to fermentation into lactate as compared to
glucose used for respiration (aerobe glycolysis). Warburg assumed this was because of irreversible injured respiration
functionality this assumption was wrong. He also assumed that oxygen deprivation will kill off cancer cells
this assumption was wrong. Modern definition of the Warburg effect: The rate of glucose uptake increases and
lactate is produced even in the presence of oxygen and fully functioning mitochondria (PET scan). Why would the
Warburg effect be beneficial for cancer cells? Proposals:
1. Rapid ATP synthesis: in glycolysis only 2ATP is produced as opposed to 30ATP for glucose oxidation. The
glycolytic rate however is 100 times faster than glucose oxidation (200ATP per unit of time for glycolysis
and 30ATP per time unit for glucose oxidation). Glycolysis is less efficient in terms of glucose usage but
produces ATP faster than glucose oxidation beneficial for cancer cells.
2. Biosynthesis: promotion of efflux into metabolic pathways (cataplerosis). Glycolysis produced a lot of
metabolites that can be used for producing DNA (nucleotides, glycerol/citrate for lipids). NADPH is also
generated by glycolysis which can be used as an antioxidant. Furthermore NADPH can be used as a
precursor for lipid production.
3. Tumour microenvironment: disruption of tissue architecture and immune cell evasion. The production of
lactate acidifies the microenvironment of the cancer cell promoting invasiveness of the cell. Furthermore
glucose usage by the tumour cell takes away glucose for the immune cells.
4. Cell signalling: ROS has a signalling function by changing the redox status of proteins, thus activating
them. It is hypothesized the ROS produced under glycolysis has a signalling function. Glycolysis also leads
to the production of Acetyl-CoA which can acetylate histones which increases transcriptional activity in the
nucleus.
The glutamine amino acid is essential for cancer cell growth and can be converted into pyruvate in the mitochondria.
Glutaminolysis contributes to lipid biosynthesis by reductive carboxylation (mitochondria IDH2/ cytoplasm
IDH1), this process in an inversed TCA cycle. Glutamate Alpha-KG isocitrate lipogenesis in the cytosol.
The reversed TCA cycle was discovered by metabolic labelling studies. The glutamine molecules where labelled
with a heavy carbon isotope, which was later discovered on the citrate product indicating reductive carboxylation.
This process takes place during hypoxia, which is common on cancer cells on the inside of a tumour. Reductive
carboxylation of glutamine allows biosynthesis (lipids, amino acids) during low concentrations of oxygen.
, Part 3 – Alternative fuels for cell function and survival
In low glucose/ hypoxic condition, cancer cells require different substrates. Three different pathways are recognized:
1. Autophagy involves degradation the cells own molecules/ cell components for survival. The process can either
be non-selective (cytosolic proteins and organelles are degraded and fused with the lysosome) or selective (cellular
components are specifically tagged (Ubiquitin) by proteins and incorporated into autophagy pathways, mitophagy for
example). The process of autophagy is required for:
the removal of damaged cell components
the recycling and redistribution of building blocks.
A cell requires growth factors, nutrients, APT production and biosynthesis a lack of these factors causes
starvation which triggers autophagy. Eventually it can lead to cell death. Autophagy is regulated by a large set ATG-
proteins which are conserved in human DNA. Phagophore formation:
1. ATG1 (ULK1) forms a complex with ATG13 and ATG17. ATG9 joins the complex which can extract lipid
membranes
2. Beclin-1 complex formation: this complex initiates the phagophore formation
3. Recruitment of other ATG proteins: ATG5/12/16 and LC3 (ATG8) which results in membrane elongation
which coats the phagophore membrane and closes it.
4. The autophagosome and lysosome fuse into a autolysosome. the acidic/ enzymatic environment of the
lysosome break down large cellular components into smaller parts which are released back into the cell.
2. Fatty acid oxidation is another
alternative fuel strategy for cancer cell
survival. Cancer stem cells are quiescent
cells in tumours that are resistant to
therapy. They have a low metabolic rate
and are designed for survival instead of
proliferation. These dormant cells are able
to renew the cancer cell pool. These
cancer stem cells rely on different fuels as
opposed to glucose and glutamine such as
fatty acid oxidation; palmitate-CoA is
turned into palmitoyl-carnitine which can
be transported by CPT1c (rate limiting
step in fatty acid oxidation) into the
mitochondria where its converted back
into palmitate-CoA which is later
incorporated into the TCA cycle as acetyl-
CoA. A knock-out of these genes slows
tumour growth in experimental
environments.
Anoikis death is a programmed cell death which should take place in cancer cells that detach from the primary
tumour, however this does not happen in these cancer stem cells (anoikis resistance). Overexpression of oncogene
ERBB2 (EGF receptor) results in higher glucose uptake in detached cells. Normal anoikis: Low glucose uptake and
growth receptor signalling low NADPH high ROS Low AMPK low FAO low ATP (The energy is
lowered and the cells will die). in detached cancer cells the glucose uptake is higher due to the EGF receptor. FAO is
upregulated and anoikis can be resisted. Furthermore antioxidants can be used by the cancer cells to decrease ROS
and increase AMPK.
3. Macropinocytosis is the uptake and catabolism of extracellular proteins to intracellular amino acids. The process
is common during amino acid starvation. In the process a protein releases a macropinosome which fuses with a
lysosome producing amino acid supply. The process differs from autophagy by producing from extracellular
materials. The process can be used as a survival tactic for cancer cells and functions as a amino acid supply for
carbon metabolism.
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