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Summary Molecular Regulation of Health and Disease (HAP-31806)
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Summary of all the lectures of the course Molecular Regulation of Health and Disease (HAP-31806)
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Summary Molecular Regulation of Health and DiseaseTheme 1 - Molecular Regulation of Energy and Nutrient Metabolism
Part1 - Cancer and metabolism
Incidence: the number of new cases of a particular disease
Death rate: number of deaths caused by a particular disease scaled to the population
Hallmarks of cancer:
Sustaining proliferative signalling
o Abnormal receptors (always activated)
o Produce their own activation signals
o Activation of downstream signalling pathways
o Lack of negative feedback loop
Evading growth suppressors
o Tumour suppressors block cell proliferation when cells are damaged (P53, Rb)
o Tumour suppressors are often mutated in cancers
Activating invasion and metastasis
o Cell undergo epithelial to mesenchymal transition
o Spread to distant sites
Enabling replicative immortality
o Altered telomeres
o Continued replication
o Immortal cells in culture
Inducing angiogenesis
o Lack of nutrients drives angiogenesis
o Activating blood vessel formation (VEGF)
o Immune cell infiltration promote angiogenesis
Resisting cell death
o Tumour cells escape programmed cell death
o Tumour cells are set to survive even when damaged
o Cell death programs are altered
Deregulation cellular energetics
Avoiding immune destruction
Tumour promoting inflammation
Genome instability and mutation
Metabolic pathways mostly exist to generate energy (ATP) or biomass (protein, DNA and membrane)
schematic overview of the most important metabolic processes in
the cell
Glycolysis: pathway where glucose is converted into pyruvate
Conversion of pyruvate into lactate: anaerobe oxidation of
pyruvate
Aerobe pyruvate oxidation in TCA: pyruvate enters TCA cycle
in mitochondria
Apart from glucose the cell needs fatty acids. The fatty acids
are transported into the cell and turned into an acylcarnitine
derivative and are oxidized in the fatty acid pathway (FAO)
ATP and NADH are generated in the glycolysis pathway and
the TCA pathway
1
, Another nutrient for the cell are amino acids. Glutamine is important for cancer cells, and is
turned into glutamate and enters the TCA cycle in the mitochondria
Both the glutamate and the TCA cycle can produce lipids. Lipids are important for
membranes
In the pentose phosphate pathway (PPP) ribonucleotides are formed, which are the basic
building blocks for DNA (NADPH is generated)
Amino acids are formed form the mitochondria and the glycolytic pathway, which can form
proteins
There are different kind of cancer cells within a
tumour, and these cells need different kinds of
metabolisms
Before angiogenesis the inner cells get little amount
of oxygen and experience metabolic stress
Proliferation:
Metabolic reprogramming to maximize:
o Biomass
o Energy (ATP)
Survival:
Metabolic reprogramming to maximize:
o Alternative fuels
o Anti-oxidant defence
Part 2 - Glucose and glutamine use in cancer and normal cells
When glucose is added to cancer cells they become acidic because they have a high lactic acid
formation
Pasteur effect: high oxygen inhibits glycolysis in yeast
Ten times as much glucose consumed in fermentation to lactate as compared to glucose consumed
during respiration (in presence of oxygen)
Warburg effect: rate of glucose uptake increases and lactate is produced even in the presence of
oxygen and fully functioning mitochondria
Cancer cells can be killed using oxygen
Why does a cancer cell benefit from the Warburg effect:
Rapid ATP synthesis
o Increases access to a limited energy source
o Glycolysis produces 2 ATP per glucose (cytoplasm)
But its glycolytic rate is much faster in cancer cells producing
200 ATP in the same time as the 30 ATP of glycose oxidation
Thus also less efficient
o Glucose oxidation produces 30 ATP per glucose (mitochondria)
Biosynthesis
o Promotes flux into biosynthetic pathways
2
, o Increased glucose utilization is used as carbon source for anabolic processes needed
to support cell growth
Tumour microenvironment
o Enhances disruption of tissue architecture and immune cell evasion
Acidification promotes invasiveness for the cell
Taking away the glucose from native immune cells
Cell signalling
o Allows for signal transduction through ROS and/or chromatin modulation
o Acetyl-CoA attaches and activates the histones, which regulates the gene activity
(transcription)
Glutamine is an amino acid and is essential for cancer cell growth
Glutaminolysis: the breakdown of glutamine into pyruvate/lactate. Occurs
in the mitochondria
Produces NADPH and NAD+
Needed for lipid synthesis
Produces purines and pyrimidines, which are needed for DNA
synthesis
Reverse TCA cycle/reductive carboxylation allows biosynthesis during hypoxia
Part 3 - Alternative fuels for cell function and survival
Alternative fuels for cancer cells
Autophagy
o Breakdown pathway
o Macroautophagy
Process of the breakdown of cell
particles into vacuoles and fuse with
the lysosome where they are
broken down and provide energy
o Selective
Mitophagy selectively degrades
mitochondria
o Nonselective
Degrades cytosolic proteins and organelles
o Normal role:
Removal of damaged parts
Recycling/redistribution of building blocks
Emergency energy supply
o Pro-survival process, but continued autophagy leads to cell death
3
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