Molecular regulation of health
and disease
THEME 1: MOLECULAR REGULATION OF ENERGY AND
NUTRIENT METABOLISM
1.1. TUMOUR VS CANCER
Tumour is not the same as cancer tumour = neoplasm. Can be, pre-malignant, malignant or
benign.
Cancer = malignant
Tumour and cancer cells display cell proliferation and rapid growth. They are capable of keeping the
cell cycle on-going. With every replication, all proteins and organelles need to be replicated too.
Which means that they require a high amount of energy and posses a profound metabolic challenge.
The high amount of energy needed usually leads to a metabolic change in cells.
Signalling pathways participate too in the metabolic rearrangement. It also allows quiescent cells to
begin to proliferate.
Metabolic changes in cancer/tumour cells are usually: high glycolysis rates, high lactate production
and high lipid biosynthesis and other macromolecules.
IMP: The main difference between cancer and tumour cells, is that not only they are capable to
uncontrollably grow but they are also invasive to other tissues. Usually via blood/lymph tissues.
1.2. CANCER CELLS
2. They are immortal survive indefinitely if nutrition is provided.
Note: cancer cells in culture can grow indefinitely, but long-term cell cultures usually have an
increased number of chromosomal aberrations and loss of functions consequently.
3. Cancer cells have loads of growth signals lower growth factor requirements to trigger
growth.
4. Cancer cells are invasive properties that support invasiveness and metastasis.
3a) loss of contact inhibition when plasma membranes come in contact with each other
they continue growing (abnormal in normal cells)
3b) Reduced cellular adhesion decreased adhesiveness and stick less than normal to each
other.
3c) Loss of anchorage dependence normal cells need to be attached to the correct rigid
substrate to grow. Cancer cells do not need that.
3d) Less organise, more mobile surface proteins de-differentiated state.
3e) altered secreted protein profile increase secretion of proteolytic enzymes. Facilitate
cell migration and invasiveness.
5. Resistant to programmed cell death (apoptosis)
6. Altered nutrient and energy metabolism increased glycolysis and lipogenesis.
Note: Cancer cells are re-programmed such that optimal growth of the individual cell is
facilitated, but at the expense of the organism to which the cancer cell belongs.
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,CANCER HALLMARKS: (8)
- Resisting cell death escaping apoptosis, set to survive when damaged.
- Inducing angiogenesis when no nutrients, activate blood vessel formation (VEGF).
- Enabling replicative immortality altered telomeres, continued replication.
- Activation of invasion and metastasis epithelial to mesenchymal transition to spread to
distant sites.
- Sustaining growth signalling abnormal receptor (always active), own activating signals,
activation of downstream signalling pathways’
- Evading of growth factors suppressors often mutated tumour suppressors.
- Evading immune destruction
- Reprogramming of energy metabolism depends on whether the state of the cancer
(proliferative/survival)
Note: cancer cells can proliferate indefinitely until certain limit like nutrient or/and oxygen
restriction.
Proliferation: Biomass production, altered glycolysis and ATP demand.
Survival: Alternative fuels and antioxidant defence.
1.3. MITOHCONDRIA AND THEIR FUNCTIONS
Mitochondria main function is the production of ATP.
Nevertheless, it responds dynamically to energy demand.
It has a role in the balanced use of energy substrates, in the urea cycle, calcium homeostasis and
amino acid metabolism.
It can also mediate apoptosis and the innate immune defence.
The oxidative signalling which is mediated by reactive oxygen species (ROS) produced in the
mitochondria, play an important role in many other functions.
GLYCOLYSIS:
Anaerobic pathways of sugar metabolism.
1 ATP´S are the result per glucose molecule + 2 pyruvate molecules.
The molecules of pyruvate can be transformed to lactate (without O2) or can enter the tricarboxylic
cycle (TCA) in the mitochondria (with O2).
High capacity, low efficiency system.
TCA CYCLE:
Pyruvate enters the mitochondria and transforms it into acetyl- CoA which is broken down to
generate CO2, NADH and FADH2.
The latter provide electrons to the respiratory chain or electron transport complexes (ETC).
NADH and FADH2 are the fuels of the 5 different complexes in the mitochondria.
The complexes oxide these molecules NAD+ and FADH is generated.
The electrons are passed to O2 to generate H2O as a side product respiration.
The proton transfer across the matrix to the into the inter-membrane space through the ATP-
synthase leads to ATP production.
Production of 32-34 more ATPs (besides the 2 ATP from previous glycolysis).
Efficient, slower and lower capability than glycolysis.
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,REACTIVE OXYGEN SPECIES (ROS):
Mitochondria is the major source of free radical or ROS species consequence of TCA cycle.
There are unpaired electrons and in interaction with O2 they generate superoxide ions (O2-) that
can be interconverted to hydroxyl ions (OH-) or being disarmed to hydrogen peroxide (H2O2).
Enzymatic systems can inactivate ROS antioxidants.
Mitochondrial ROS significant physiological signalling function and role in maintaining
homeostasis.
However, they can be very harmful too DNA damage, cell membrane damage, lipid peroxidation.
In healthy cells, when there are pathogenic levels of ROS; the cell enters apoptosis.
ROS is increased if higher pyruvate influx, decreased ATP demand and increased membrane
potential.
1.4. REPROGRAMMING OF THE METABOLISM
REPROGRAMMING THE GLYCOLYTIC METABOLISM
Growth factor signalling regulates the uptake and metabolism of extracellular nutrient in normal
cells growth and replication.
Cancer cells growth factor independent, however machinery that promotes rapid growth.
This image depicts the two possibilities
of cells. Lineage specific growth factor
signalling, at rest, the cells can uptake as
many nutrients as needed to maintain
basal levels of nutrients required for the
smooth cell mechanism.
However, when there are no extrinsic
signals (no ligands) available, the cells
enter a survival mode, that is relying on
recycling on macromolecules and
organelles in a process called auto
phagocytosis. Which eventually results in cell death (lower side of the scheme).
However, increasing ligand signalling instructs the cells to begin taking up nutrients at a high rate and
to allocate them into metabolic pathways that support biomass production and ultimately the
formation of new daughter cells. (higher side of the scheme).
In the 20s´, Otto Warburg already investigated that cancer cells relies mainly on glycolysis for ATP
uptake, even under aerobic conditions. Nevertheless, further studies revealed that cancer cells do
respire and produce ATP too, and that this is not due to unpaired mitochondria, as previously
hypothesized.
Warburg effect due to alterations in signalling pathways that govern glucose uptake and
utilization, not by mitochondrial defect per se.
The ATP utilization by cancer cells is now widely used for cancer tumour visualization throughout PET
(positron emission tomography).
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, High glycolysis rate = High glucose influx= high conversion to pyruvate= high number of substrates for
lipid, amino acid, and DNA synthesis.
Specifically: NADPH, ribose, acetyl-CoA, and glucose-derived non-essential amino acids.
+ Why does Warburg effect occur?
High glycolytic rate provides many advantages towards the
development and cell growth of cancer cells:
1. Glucose is fast and obtain in high concentration to generate
ATP.
Note: glycolysis produces much less ATP than the TCA cycle but
in can be increased up to x100 faster
2. Glucose degradation provides cells with intermediates needed
for biosynthetic pathways ribose sugars for nucleotides,
glycerol and citrate for lipids and non-essential amino acids
and NADPH for antioxidant defence and biosynthesis
Pentose-phosphate pathway.
3. Glycolysis requires less cellular volume and proteins.
4. Tumour microenvironment enhances disruption of tissue
architecture and immune cell evasion by lowering ph.
5. Cell signalling allows for signal transduction through ROS and/or chromatin modulation.
Nucleosomes are regulated and opened by acetylation. Acetyl metabolite comes from
Acetyl-CoA produced in the mitochondria and added by acetyl-CoA transferases. Therefore,
leading to a more open DNA for transcription.
Disadvantages:
1. Waste products such as lactate acidic environment(more) permissive for cancer cells.
Lactate is produced instead of entering the TCA cycle because of ROS reduction and NAD+
regeneration., via lactate dehydrogenase A (LDHA).
If high pyruvate and limited O2 = ROS activation.
Conversion of pyruvate to lactate restores NAD+.
LDHA is induced by oncogenes, growth factor stimulation in lymphocytes and hypoxia.
THE TCA CYCLE PROVIDES PRPOLIFERATING CELLS WITH
BIOSYNTHTIC PRECUSORS
In cancer cells the TCA cycle is derived for a hub of biosynthesis of molecules for cell growth
continuous efflux of intermediates (cataplerosis).
Process:
- Pyruvate enters the mitochondria and is converted to acetyl-CoA.
- Acetyl-CoA enters the TCA cycle and produces citrate.
- Citrate exist the mitochondria and is converted back to acetyl-CoA by ACYL enzyme (ATP
citrate lyase).
- Acetyl-CoA with NADH can be converted to malonyl-CoA and subsequently to palmitoyl CoA
by the enzyme FASN (Fatty acid synthesase).
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