Cell metabolism & cancer Flashcards
what was Boveris theory of the origin of cancer cells?
Theodore Boveri theorised that they arose from mutations in the genetic code
(he saw aberrant nuclei in cancer cells
what was Warburgs theory of the origin of cancer cells?
Otto Warburg theorised that the driver of tumorigenesis is an insufficient cellular respiration caused by insult to mitochondria.
who was right Boveri or Warburg?
Both Boveri and Warburg were correct in their assumptions that genetics and metabolism respectively are important in cancer: DNA mutations alter metabolism and metabolism alters gene expression
what is positron emission tomography imaging with 18fluoro-deoxyglucose (FDG-PET)?
how can in be used in the treatment/monitoring of cancer?
an imaging method that identifies locations of high glycolytic activity via FDG
Initially used in brain biology
(bladder heart and brain can also show up)
can be used to monitor the glycolytic levels arfter a particular therapy to determine - can predict long term responses of patients to cancer therapy (eg if they take up less glucose then they could have fewer tmour cells or be less glycolytic which is positive)
what did
18FDG-PET in breast cancer subtypes
show us
that they is a correlation between aggressive subtypes and more glycolysis
what is the Warburg effect?
The Warburg Effect is defined as an increase in the rate of glucose uptake and preferential production of lactate, even in the presence of oxygen in cancer cells
- switching of the cell from the normal respiratory pathway to aerobic glycolysis
Aerobic glycolysis in the invasive cells is greater than hypoxia-induced (aerobic) glycolysis in the non-invasive line
what is the Pasteur effect?
The Pasteur effect reflects the marked difference in cellular capacity for ATP production in the presence and absence of oxygen
in the absence of oxygen (anaerobic conditions) cells depend on what for ATP production
glycolysis
ultimately what would happen if a cell didnt have ATP
On the cell membrane are ATP dependent sodium transporters for osmosis regulation – these need energy, if you run out of ATP the cell swells and bursts
What is the hypothesis of hydroxia mediated selection?
once a tumour outgrows it blood supply and cant get enough oxygen, the cells begin hypoxia driven glycolysis. If they are genetically driven to undergo elevated glycolysis anyway then they will grow better and are the more likely cell line to survive
‘increase aerobia glycolysis makes the tumour cell more able to survive periods of low oxygen availability’ warburg 1956, gatenby&giles 2004
why does the cancer become acidic after it becomes adapted to the low oxygen conditions and how does this help invasion?
because glycolysis causes lactate build up
this further changes the cell biology and drives EMT
what changes in tumour cells result in them having high rates of anaerobic glycolysis
‘damage to respiration’ & ‘increase in the fermentation’
reversible/ irreversible
reversible:
- biochemical
- gene expression
- HIF1α activation
irreversible:
- FH and SDH mutations
- VHL mutations
how/when are HIFs activated?
When oxygen levels are low, Hypoxia Inducible Factors (HIFs) accumulate and bind to gene promotors.
This occurs because they are no longer being ubiquitinised and degraded. In normal conditions PHDs (O2 dependent prolyl hydroxylases) hydroxylate HIF1α, which recruits pVHL, targeting HIF1α for proteosome-dependent degredation)
oxygen depletion activate HIFα increasing expression of glycolytic genes
Whats the function of HIFs?
HIFs bind to the promoters of genes such as GLUT1, GLUT3, HK-2, PFK-2, PK2, LDHA, MCT4, PDK-1
These contribute to glycolysis, shut down oxidative phosphorylation in mitochondria, stop O2 & ATP consumption and increase blood supply - all things that help make the cancer more tolerant
gives two examples of reversible regulation of glycolysis?
Biochemically lactate production is part of the normal process some of the pyruvate will be converted into lactate. Anaerobic glycolysis is the transformation of glucose to lactate occurs when limited amounts of oxygen (O2) are available
Gene expression and HIF1α activation: activated by depletion of oxygen levels, but when oxygen comes back PHDs will direct their degredation and the process will go back to normal. HIFs bind to the promoters of glycolytic genes
give two examples of irreversible regulation of glycolysis
mutations of fumarate hydratase (FH) and succinate dehydrogenase (SDH) - causes impaired mitochondrial synthesis of ATP, fumarate and succinate accumulate which inactivates PHDs causing increased HIFα which increase glycolysis and other hallmarks of cancer
mutations in VHL - VHL is a tumour suppressor gene that targets HIFα for degredation. therefore mutations cause an accumulation of HIFα increasing glycolysis
both lead to pseudohypoxia
what is a major difference in the control of proliferation between unicellulat and multicellular organisms
In a unicellular organism control of proliferation is by whether there are nutrient or not
In multicellular organisms there is always enough nutrients so proliferation is controlled by growth signals
whats the difference in ATP production between differentiated tissue and proliferative tissue/ tumor?
differentiated tissue uses glucose to do oxidative phosphorylation in presence of O2 (36 ATP/mol) and anaerobic glycolysis in absence of O2 (2 ATP /mol)
tumors and proliferative tissue uses aerobic glycolysis in the presence or absence of O2 (4 ATP/mol)
why is lactate needed?
to regenerate NADH
what are the benefits of glycolysis in a proliferating cell?
- Glycolysis is inefficient, but it is fast, allowing rapid proliferation.
- The waste product (lactate) is recycled to glucose by the liver (Cori cycle) so is not wasted by the organism.
- This “makes sense” for the organism where localised rapid cell division is required for wound healing or an immune response. [Also embryogenesis]
What is Pyruvate kinase M2?
catalyzes the final reaction of glycolysis, in which the high-energy phosphate group is transferred from phosphoenolpyruvate (PEP) to ADP to form Pyruvate, with the production of ATP
specifically found in proliferating cells (eg tumour and embryonic)
expression of PKM2 is up-regulated in most of the cancer cells
what does the pentose phosphate pathway do for the cell
makes NADPH for anabolic pathways and ROS protection
in addition to helping DNA & RNA synthesis
how do mitochondria generate harmful reactive oxygen species?
- Pyruvate enters the mitochondria as Acetyl-CoA
- This enters the TCA cycle where electrons (energy) are donated to NAD+ and FAD to generate NADH and FADH2
- Electrons from NADH and FADH2 are passed through the electron transport chain to generate the mitochondrial membrane proton gradient that drive ATP synthase
- Respiratory complexes leak electrons to oxygen to produce superoxide O2-
these can lead to damage to nucleic acids, lipids and proteins
superoxide O2- production increases when ETC activity is…
more than ATP demand
