Theme 1 - Molecular regulation of energy and nutrient
metabolism
- Tumour vs cancer –
Cancer: a group of cells display uncontrolled growth and invasion that
intrudes and destroys adjacent tissues or spreading to other locations in
the body via lymph or blood.
- Malignant
Tumour: doesn’t have the malignant properties of cancers. They do not
invade or metastasize.
- benign, pre-malignant, malignant or represent a lesion with no
cancerous potential.
Cell proliferation required for embryogenesis, growth, proper function of
tissues and tumorigenesis.
Tumour and cancer cells display cell proliferation and rapid growth.
- Proliferating cells take up nutrients in excess of bioenergetic needs and
shunt metabolites into biosynthetic pathways
Proliferation can cause problems in cellular metabolism.
- Each passage through the cell cycle yields 2 daughter cells and requires
a doubling of total biomass (proteins, lipids, nucleic acids). > metabolic
challenge.
Metabolism in proliferating cells differs from quiescent cell metabolism by
high rates of glycolysis, lactate production and increased biosynthesis of
lipids.
- Cancer cells –
Cell transformation: proces of cell change, in which a cell loses its
ability to control its rate of division and thus becomes a tumour cell.
- The tumour cell retains the structural and functional characteristics of
the normal cell type from which it is derived.
Cancer cells differ from their normal counterparts in several aspects:
Cancer cells are immortal cells can grow indefinitely
Cancer cells display sufficiency in growth signals display lower
growth factor requirements
Cancer cells are invasive and have properties that support invasion and
metastasis
- loss of contact inhibition they do not stop growing when their
plasma membranes come into contact with one another.
- reduced cellular adhesion decreased adhesiveness and stick to
each other less than normal cells.
- less organized, more mobile surface proteins.
, - altered secreted protein profile increased secretion of proteolytic
enzymes, which facilitates cell migration and invasiveness.
Cancer cells are resistant to programmed cell death (apoptosis)
Cancer cells have an altered nutrient and energy metabolism
- increased rate of glycolysis corresponding increase in lactic acid
production in cells. Measured with PET imaging of cancerous tissue.
- more negative surface charge of cell membrane and sustained
angiogenesis. supports nutrient uptake.
Cancer cells are re-programmed such that optimal growth of the individual
cell is facilitated but are the expense of the organism to which the cancer
cell belongs.
Hallmarks of cancer:
Sustaining proliferative signaling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
Evading immune destruction
Reprogramming of energy metabolism
Cancer cells alter nutrient and energy metabolism.
- Mitochondria –
Mitochondria: organelles that reside in eukaryotic cells.
- Double membrane mitochondrial outer membrane (MOM) and
mitochondrial inner membrane (MIM).
- Mitochondrial function is substantially altered in cancer cells
Most mitochondrial proteins are encoded by nuclear DNA and imported
into mitochondria via the translocator of outer membrane (TOM) and
translocator of inner membrane (TIM) complexes.
Functions of mitochondria
Production of ATP from substrates (lipids, pyruvate, amino acids).
respond to cellular energy requirements
Mitochondria have roles in:
balanced use of energy substrates (lipids, sugars, amino acids)
urea cycle
calcium homeostasis
amino acid metabolism
Mitochondria are essential for and mediate:
heme and iron sulphur cluster biosynthesis
apoptosis
, innate immune defense
oxidative signaling > mediated by reactive oxygen species (ROS) that
are produced in mitochondria.
- Glycolytic metabolism, electron transport complexes (ETC)
and oxidative phosphorylation (OXPHOS) –
Sugars are metabolized in glycolysis.
- Anaerobic
- Provides 2 molecules of ATP per molecule glucose
- High capacity/low efficiency
- End product 2 molecules pyruvate (imported in mitochondria) or 2
molecules lactate
Pyruvate: conversion in acetyl CoA by pyruvate dehydrogenase and then
feeds into TCA cycle.
Enzyme system of TCA cycle breaks down acetyl CoA (derived from
pyruvate), fatty acid and amino acid breakdown, to generate CO2.
- In this process reduces NAD+ to NADH and FAD to FADH 2. > provide
electrons to respiratory chain or electron transport complexes (ETC).
Respiratory chain consists of 4 complexes:
1) NADH dehydrogenase
2) Succinate dehydrogenase
3) Cytochrome c reductase
4) Cytochrome c oxidase
There is a transfer of energy between the intermediates of the respiratory
chain, from a reduced to an oxidized state.
1) Electrons from NADH to complex 1 or from TCA derived FADH2 to
complex 2
2) Electrons transferred from either of these complexes to ubisemiquinone
(co-enzyme Q), which shuttles electrons to complex 3.
- Electrons from beta-oxidation feeds via FTP to co-enzyme Q and to
complex 3.
3) Cytochrome C shuttles electrons from complex 3 to complex 4.
- Electrons are transferred to oxygen to form H2O.
Respiration: the use of oxygen at complex 4. aerobic respiration.
- Efficient way to produce ATP, but capacity of glycolytic metabolism can
be higher.
Transport electrons accompanied by transfer of protons across
mitochondrial inner membrane. key to establishing electrochemical
proton gradient.
- Inward movement of protons results in phosphorylation of ADP to form
ATP.
metabolism
- Tumour vs cancer –
Cancer: a group of cells display uncontrolled growth and invasion that
intrudes and destroys adjacent tissues or spreading to other locations in
the body via lymph or blood.
- Malignant
Tumour: doesn’t have the malignant properties of cancers. They do not
invade or metastasize.
- benign, pre-malignant, malignant or represent a lesion with no
cancerous potential.
Cell proliferation required for embryogenesis, growth, proper function of
tissues and tumorigenesis.
Tumour and cancer cells display cell proliferation and rapid growth.
- Proliferating cells take up nutrients in excess of bioenergetic needs and
shunt metabolites into biosynthetic pathways
Proliferation can cause problems in cellular metabolism.
- Each passage through the cell cycle yields 2 daughter cells and requires
a doubling of total biomass (proteins, lipids, nucleic acids). > metabolic
challenge.
Metabolism in proliferating cells differs from quiescent cell metabolism by
high rates of glycolysis, lactate production and increased biosynthesis of
lipids.
- Cancer cells –
Cell transformation: proces of cell change, in which a cell loses its
ability to control its rate of division and thus becomes a tumour cell.
- The tumour cell retains the structural and functional characteristics of
the normal cell type from which it is derived.
Cancer cells differ from their normal counterparts in several aspects:
Cancer cells are immortal cells can grow indefinitely
Cancer cells display sufficiency in growth signals display lower
growth factor requirements
Cancer cells are invasive and have properties that support invasion and
metastasis
- loss of contact inhibition they do not stop growing when their
plasma membranes come into contact with one another.
- reduced cellular adhesion decreased adhesiveness and stick to
each other less than normal cells.
- less organized, more mobile surface proteins.
, - altered secreted protein profile increased secretion of proteolytic
enzymes, which facilitates cell migration and invasiveness.
Cancer cells are resistant to programmed cell death (apoptosis)
Cancer cells have an altered nutrient and energy metabolism
- increased rate of glycolysis corresponding increase in lactic acid
production in cells. Measured with PET imaging of cancerous tissue.
- more negative surface charge of cell membrane and sustained
angiogenesis. supports nutrient uptake.
Cancer cells are re-programmed such that optimal growth of the individual
cell is facilitated but are the expense of the organism to which the cancer
cell belongs.
Hallmarks of cancer:
Sustaining proliferative signaling
Evading growth suppressors
Resisting cell death
Enabling replicative immortality
Inducing angiogenesis
Activating invasion and metastasis
Evading immune destruction
Reprogramming of energy metabolism
Cancer cells alter nutrient and energy metabolism.
- Mitochondria –
Mitochondria: organelles that reside in eukaryotic cells.
- Double membrane mitochondrial outer membrane (MOM) and
mitochondrial inner membrane (MIM).
- Mitochondrial function is substantially altered in cancer cells
Most mitochondrial proteins are encoded by nuclear DNA and imported
into mitochondria via the translocator of outer membrane (TOM) and
translocator of inner membrane (TIM) complexes.
Functions of mitochondria
Production of ATP from substrates (lipids, pyruvate, amino acids).
respond to cellular energy requirements
Mitochondria have roles in:
balanced use of energy substrates (lipids, sugars, amino acids)
urea cycle
calcium homeostasis
amino acid metabolism
Mitochondria are essential for and mediate:
heme and iron sulphur cluster biosynthesis
apoptosis
, innate immune defense
oxidative signaling > mediated by reactive oxygen species (ROS) that
are produced in mitochondria.
- Glycolytic metabolism, electron transport complexes (ETC)
and oxidative phosphorylation (OXPHOS) –
Sugars are metabolized in glycolysis.
- Anaerobic
- Provides 2 molecules of ATP per molecule glucose
- High capacity/low efficiency
- End product 2 molecules pyruvate (imported in mitochondria) or 2
molecules lactate
Pyruvate: conversion in acetyl CoA by pyruvate dehydrogenase and then
feeds into TCA cycle.
Enzyme system of TCA cycle breaks down acetyl CoA (derived from
pyruvate), fatty acid and amino acid breakdown, to generate CO2.
- In this process reduces NAD+ to NADH and FAD to FADH 2. > provide
electrons to respiratory chain or electron transport complexes (ETC).
Respiratory chain consists of 4 complexes:
1) NADH dehydrogenase
2) Succinate dehydrogenase
3) Cytochrome c reductase
4) Cytochrome c oxidase
There is a transfer of energy between the intermediates of the respiratory
chain, from a reduced to an oxidized state.
1) Electrons from NADH to complex 1 or from TCA derived FADH2 to
complex 2
2) Electrons transferred from either of these complexes to ubisemiquinone
(co-enzyme Q), which shuttles electrons to complex 3.
- Electrons from beta-oxidation feeds via FTP to co-enzyme Q and to
complex 3.
3) Cytochrome C shuttles electrons from complex 3 to complex 4.
- Electrons are transferred to oxygen to form H2O.
Respiration: the use of oxygen at complex 4. aerobic respiration.
- Efficient way to produce ATP, but capacity of glycolytic metabolism can
be higher.
Transport electrons accompanied by transfer of protons across
mitochondrial inner membrane. key to establishing electrochemical
proton gradient.
- Inward movement of protons results in phosphorylation of ADP to form
ATP.
