Cancer Metabolism Flashcards
What is the Warburg effect?
One of the first identified biochemical distinctions of cancer cells in 1930 by Otto Warburg
Even in the presence of oxygen, cancer cells can reprogram their glucose metabolism, and thus their energy production, by limiting their energy metabolism largely to glycolysis, leading to a state that has been termed ‘‘aerobic glycolysis.’’
What is oxidative phosphorylation?
In the presence of oxygen, non-proliferating (differentiated) tissues first metabolize glucose to pyruvate via glycolysis and then completely oxidize most of that pyruvate in the mitochondria to CO2 during the process of oxidative phosphorylation. Only a very small amount of pyruvate is converted to lactate instead.
Because oxygen is required as the final electron acceptor to completely oxidize the glucose, oxygen is essential for this process. This produces a net gain of ~36 mol ATP/mol glucose.
What is anaerobic glycolysis?
When oxygen is limiting, cells can redirect the pyruvate generated by glycolysis away from mitochondrial oxidative phosphorylation by generating lactate (anaerobic glycolysis).
This generation of lactate during anaerobic glycolysis allows glycolysis to continue (by cycling NADH back to NAD+ - the oxidised cofactor being required for glycolysis).
However, this results in minimal ATP production when compared with oxidative phosphorylation; more specifically, 2 mol ATP/mol glucose vs. 36 mol ATP/mol glucose.
What is aerobic glycolysis?
Warburg observed that cancer cells tend to convert most glucose to lactate regardless of whether oxygen is present (aerobic glycolysis). This property is shared by normal proliferative tissues.
Mitochondria remain functional and some oxidative phosphorylation continues in both cancer cells and normal proliferating cells. Nevertheless, aerobic glycolysis is less efficient than oxidative phosphorylation for generating ATP, giving a net gain of 4 mol ATP/mol glucose.
How is glucose utilised in proliferating cells?
Proliferating cells tend to favour aerobic glycolysis.
In proliferating cells, ~10% of the glucose is diverted into biosynthetic pathways upstream of pyruvate production.
Why did research into cancer metabolism wane?
Discoveries in the late 1970s and early 1980s revealed that cancers could result from mutation, and none of the early oncogenes or tumor suppressor genes were metabolic enzymes.
Studies in the 1960s and 1970s also revealed exceptions to the Warburg observation.
More recently however, several metabolism-related oncogenes/TS have been identified renewing interest in its viability as a therapy target.
How and why is AMP used as the sensor for energy state?
The levels of ATP and ADP are poor indicators of the energy state of the cell. Due to the action of adenylate kinase, the ATP levels tend not to decrease much during high-energy requirement and the ADP levels stay constant and low. However, the AMP product of this reaction leads to fast and proportionally huge increase in AMP level, making it a useful sensor.
In order to regulate metabolism, AMP stimulates AMPK to mediate its effects rather than acting on all the metabolic enzymes individually.
What is the structure of AMPK?
• AMPK has three subunits: α, β and γ
o The α subunit has a kinase domain
o The γ subunit is where both AMP and ATP bind - The γ subunit has an AMP/ATP binding domain
How is AMPK regulated?
- When ATP is bound to the γ subunit AMPK is inactive
- When ATP levels decrease or AMP levels increase, i.e. a cell is running out of energy, LKB1 or other AMP sensitive kinases phosphorylate AMPK to make it fully active and make the system more sensitive to [AMP]
What effect does active AMPK have?
AMPK phosphorylates many metabolic enzyme targets, to switch off ATP-consuming synthases and upregulate processes that increase ATP.
It also regulates TFs that lead to longer term up or downregulation of metabolic processes at the expression level.
Which signalling pathway is a primary regulator of metabolism? How is this activated?
The PI3K/Akt pathway.
The insulin/other RTK arms on the receptor are recognised by PI3K, a dimeric protein composed of p85 (the subunit that binds the RTK via SH2 domains) and p110 (the kinase).
How does PI3K potentiate the Akt signalling pathway?
PI3K is a lipid kinases, adding a third phosphate onto phosphatidyl-inositol (4, 5) kinase (PIP2) in the 3’ position, while it is embedded in the membrane by its phospholipid tail, producing PIP3 (phosphatidyl inositol 3, 4, 5 kinase).
This sugar ring is recognised by the Pleckstrin Homology Domains present on PDK1/2 and Akt, localising both of them to the membrane so that PDK1 can double-phosphorylate Akt (AKA PKB) at Thr-308 and Ser-473, activating it.
What effect does the PI3K pathway have?
Akt responds to the signal by stimulating changes in two different categories, energy metabolism and growth response, often via mTOR signalling.
Since it is a response to increased insulin, amongst other things, it should come as no surprise that Akt increases the cells glucose uptake and activates glycogen synthesis while inhibiting glycogenolysis and lipolysis.
It specifically targets;
• Protein Synthesis Machinery
• Enzymes catalyzing glycogen metabolism
• Enzymes catalyzing glycolysis and oxidative phosphorylation - Cancer and Warburg Effect
How does cap-dependent translation initiation begin?
The cap is mostly comprised of eIFs (Eukaryotic Initiation Factors) that bind to the 7-methly guanosine cap on one end of the mRNA.
The first protein to bind is eIF4E, which then recruits eIF4G. eIF4G binds to both eIF4A/B – which are responsible for binding to the ribosome – and PABP (PolyA Binding Protein) that circularises the mRNA. Ensuring that the mRNA is complete and increasing the local concentration of important factors.
What happens in cap-dependent translation initiation after circularisation?
Formation of the 43S complex occurs.
This is the 40S ribosome subunit complexed with a GTP-linked tRNA and eIF1, 1A, 2, 3 and 5 (known together as the Ternary Complex).
eIF1A is responsible for generating a pool of 40S subunits, and with eIF3 binds the ternary complex to the 40S ribosome subunit producing the 43S complex.
The 43S complex is responsible for scanning for the Kozak sequence.
