SUMMARY Molecular regulation of health and disease HAP-31806
THEME 1 – Molecular regulation of energy and nutrient metabolism
Part 1: Cancer and metabolism
Hallmarks of cancer:
- Sustaining proliferative signaling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
Sustaining growth signaling:
- Abnormal receptors (always activated)
- Produce their own activation signals
- Activation of downstream signaling pathways
Resisting cell death:
- Tumor cells escape programmed cell death
- Tumor cells are set to survive even when damaged
- Cell death programs are altered
Evading anti-growth:
- Tumor suppressors block cell proliferation when cells are damaged (P53, Rb)
- Tumor suppressors are often mutated in cancers
Replication potential:
- Altered telomerases: instead of shortening (normal cells) -> enhancement of
telomerase activity -> synthesis and extension of telomeric DNA ->
- Continued replication
- Immortal cells in culture
Angiogenesis:
- Lack of nutrients drives angiogenesis
- Activating blood vessel formation (VEGF)
- Immune cell infiltration promotes angiogenesis
Invasion / metastasis:
- Cells undergo epithelial to mesenchymal transition -> spread to distant sites
Other hallmarks:
- Avoiding immune destruction
- Tumor promoting inflammation
- Genome instability and mutation
- Deregulation cellular energetics
Metabolic hallmarks: sustaining proliferation signaling deregulating cellular energetics
1
,Cell metabolism makes biomass and energy:
Biomass = protein, DNA, membrane; Energy = ATP
Glycolysis: glucose -> pyruvate
Anaerobe oxidation of pyruvate: pyruvate -> lactate
Aerobe oxidation of pyruvate in TCA: pyruvate -> lactate
FA oxidation: FA -> FAO -> into TCA (FAO en TCA in mitochondrion)
ATP and NASH are generated: glucose – ATP → pyruvate
Glutaminolysis: glutamine -> glutamate -> TCA
Lipogenesis for membranes: lipids from TCA and glutamate ->
membrane
PPP to DNA: from glycolysis -> PPP -> ribonucleotides -> DNA
AA used for protein synthesis
Cancer cell metabolism
Proliferation: metabolic reprogramming to maximize: biomass, energy (ATP)
Survival: metabolic reprogramming to maximize: alternative fuels, anti-oxidants defense
Part 2: Glucose and glutamine use in cancer and normal cells
The Warburg effect:
Warburg experiment: + glucose; - glucose
- glucose with cells; + glucose with cells; + glucose no cells
- pH decreased= acidification
- measurement: pressure decrease = O2 consumption
o pressure increase = CO2 production
▪ lactic acid exchanges protons with bicarbonate to form CO2
2
,Warburg’s first discovery: tumors have high rate of lactic acid formation
Pasteur effect: high O2 inhibits glycolysis in yeast (in culture)
Second experiment: according to Pasteur effect, when O2 present -> no glycolysis but that
was not what Warburg saw:
- 10x more glucose consumed in fermentation to lactate as compared to glucose
consumed during respiration (in the presence of oxygen)
- Aerobe glycolysis (glycolysis in the presence of oxygen) -> thus, tumor cells have
glycolysis in the presence of oxygen
Why did Warburg thought that mitochondria are dysfunctional in cancer cells: normal cells
can lower glycolysis when using mitochondria, and cancer cells cannot -> reasoned because
mitochondria are damaged.
Purpose of mitochondria in cancer cells: mitochondria are essential for making building
blocks but also for making NADH and regenerating NAD>
Upregulated enzymes and genes from the glycolytic pathway regulate the Warburg effect.
Warburg effect: rate of glucose uptake increases, and lactate is produced even in the
presence of oxygen and fully functioning mitochondria.
The benefits of the Warburg effect on cancer cells:
Rapid ATP synthesis:
Glycolysis: glu -> pyruvate -> lactate + 2 ATP
Glucose oxidation: glu -> pyruvate -> CO2/H20 + ~30 ATP
→ glycolysis responds to increasing ATP demand
3
, Biosynthesis:
Increased glucose utilization is used as carbon source for anabolic processes needed to
support cell growth
Glycolytic pathway is needed to build DNA
PPP: G6P/F6P/G3P -> turn into ribose; 3PG -> turn into glycine
Ribose and glycine are precursors for nucleotides -> DNA
PPP: also produces NADPH = essential for biosynthetic pathways and antioxidant defense
Tumor microenvironment:
Altering the tumor microenvironment:
- Acidification promotes invasiveness
- Taking away the glucose from native immune cells (glucose competition)
Cell signalling:
Inactive transcription / active transcription (by histone acetylation)
Glutamine and cancer cell metabolism
Glutamine = essential metabolite for cancer cells (growth)
Glutaminolysis = breakdown of glutamine to pyruvate / lactate -> via mitochondria
(glycolysis is in cytosol)
Pyruvate and glutamate -> building blocks for membranes
Reductive carboxylation: not losing the isotype -> is incorporated into
citrate and other metabolites as oxaloacetate (OAA)
→ allows biosynthesis during hypoxia
Glutamine into lipids via 1) cytosolic route or via 2) mitochondrial route
2. mitochondrial route: reductive carboxylation of alpha-kG into citrate
4
THEME 1 – Molecular regulation of energy and nutrient metabolism
Part 1: Cancer and metabolism
Hallmarks of cancer:
- Sustaining proliferative signaling
- Evading growth suppressors
- Activating invasion and metastasis
- Enabling replicative immortality
- Inducing angiogenesis
- Resisting cell death
Sustaining growth signaling:
- Abnormal receptors (always activated)
- Produce their own activation signals
- Activation of downstream signaling pathways
Resisting cell death:
- Tumor cells escape programmed cell death
- Tumor cells are set to survive even when damaged
- Cell death programs are altered
Evading anti-growth:
- Tumor suppressors block cell proliferation when cells are damaged (P53, Rb)
- Tumor suppressors are often mutated in cancers
Replication potential:
- Altered telomerases: instead of shortening (normal cells) -> enhancement of
telomerase activity -> synthesis and extension of telomeric DNA ->
- Continued replication
- Immortal cells in culture
Angiogenesis:
- Lack of nutrients drives angiogenesis
- Activating blood vessel formation (VEGF)
- Immune cell infiltration promotes angiogenesis
Invasion / metastasis:
- Cells undergo epithelial to mesenchymal transition -> spread to distant sites
Other hallmarks:
- Avoiding immune destruction
- Tumor promoting inflammation
- Genome instability and mutation
- Deregulation cellular energetics
Metabolic hallmarks: sustaining proliferation signaling deregulating cellular energetics
1
,Cell metabolism makes biomass and energy:
Biomass = protein, DNA, membrane; Energy = ATP
Glycolysis: glucose -> pyruvate
Anaerobe oxidation of pyruvate: pyruvate -> lactate
Aerobe oxidation of pyruvate in TCA: pyruvate -> lactate
FA oxidation: FA -> FAO -> into TCA (FAO en TCA in mitochondrion)
ATP and NASH are generated: glucose – ATP → pyruvate
Glutaminolysis: glutamine -> glutamate -> TCA
Lipogenesis for membranes: lipids from TCA and glutamate ->
membrane
PPP to DNA: from glycolysis -> PPP -> ribonucleotides -> DNA
AA used for protein synthesis
Cancer cell metabolism
Proliferation: metabolic reprogramming to maximize: biomass, energy (ATP)
Survival: metabolic reprogramming to maximize: alternative fuels, anti-oxidants defense
Part 2: Glucose and glutamine use in cancer and normal cells
The Warburg effect:
Warburg experiment: + glucose; - glucose
- glucose with cells; + glucose with cells; + glucose no cells
- pH decreased= acidification
- measurement: pressure decrease = O2 consumption
o pressure increase = CO2 production
▪ lactic acid exchanges protons with bicarbonate to form CO2
2
,Warburg’s first discovery: tumors have high rate of lactic acid formation
Pasteur effect: high O2 inhibits glycolysis in yeast (in culture)
Second experiment: according to Pasteur effect, when O2 present -> no glycolysis but that
was not what Warburg saw:
- 10x more glucose consumed in fermentation to lactate as compared to glucose
consumed during respiration (in the presence of oxygen)
- Aerobe glycolysis (glycolysis in the presence of oxygen) -> thus, tumor cells have
glycolysis in the presence of oxygen
Why did Warburg thought that mitochondria are dysfunctional in cancer cells: normal cells
can lower glycolysis when using mitochondria, and cancer cells cannot -> reasoned because
mitochondria are damaged.
Purpose of mitochondria in cancer cells: mitochondria are essential for making building
blocks but also for making NADH and regenerating NAD>
Upregulated enzymes and genes from the glycolytic pathway regulate the Warburg effect.
Warburg effect: rate of glucose uptake increases, and lactate is produced even in the
presence of oxygen and fully functioning mitochondria.
The benefits of the Warburg effect on cancer cells:
Rapid ATP synthesis:
Glycolysis: glu -> pyruvate -> lactate + 2 ATP
Glucose oxidation: glu -> pyruvate -> CO2/H20 + ~30 ATP
→ glycolysis responds to increasing ATP demand
3
, Biosynthesis:
Increased glucose utilization is used as carbon source for anabolic processes needed to
support cell growth
Glycolytic pathway is needed to build DNA
PPP: G6P/F6P/G3P -> turn into ribose; 3PG -> turn into glycine
Ribose and glycine are precursors for nucleotides -> DNA
PPP: also produces NADPH = essential for biosynthetic pathways and antioxidant defense
Tumor microenvironment:
Altering the tumor microenvironment:
- Acidification promotes invasiveness
- Taking away the glucose from native immune cells (glucose competition)
Cell signalling:
Inactive transcription / active transcription (by histone acetylation)
Glutamine and cancer cell metabolism
Glutamine = essential metabolite for cancer cells (growth)
Glutaminolysis = breakdown of glutamine to pyruvate / lactate -> via mitochondria
(glycolysis is in cytosol)
Pyruvate and glutamate -> building blocks for membranes
Reductive carboxylation: not losing the isotype -> is incorporated into
citrate and other metabolites as oxaloacetate (OAA)
→ allows biosynthesis during hypoxia
Glutamine into lipids via 1) cytosolic route or via 2) mitochondrial route
2. mitochondrial route: reductive carboxylation of alpha-kG into citrate
4
