Cell Metabolism Flashcards
Emerging hallmark of cancer
Dysregulation of cellular energetics.
What is the Warburg Effect?
Even in aerobic conditions, cancer cells tend to favor metabolism via glycolysis rather than the oxidative phosphorylation pathway.
Basic steps of glucose metabolism.
Glucose supplied by blood, Uptake by glucose transporter
Hexokinase converts glucose into G-6-P
Follows glycolysis cascade
Ends as Pyruvate
Either to mitochondria for ETC or converted to lactate
How can PET be used to show the spread of cancer and location of nodes in the body?
Positron emission tomography
Use 18FDG, an analogue of glucose that can be taken up by cells, but not processed.
Quantifiable measurements show aggressiveness of cancer forms.
How do tumour cells survive in hypoxic conditions.
They produce ATP from glycolysis due to the lack of oxygen, needed for the ETC. Tumour cells uptake more glucose for the same amount of ATP produced.
Increased aerobic glycolysis make the tumour more capable of surviving periods of low oxygen availability, as it is already primed for glycolysis.
Hypoxia mediated selection for cells that have the best glycolysis capabilities.
What is the reversible biochemical change in cancer cells that increase the glycolysis rates under hypoxic conditions?
Phosphofructokinase 1 (PFK1) converts F6P int F1,6P.
Activated by AMP.
When ADP is converted to ATP and AMP in anaerobic conditions, AMP activated PFK1 to pass glucose through the ATP generating steps of glycolysis.
Pyruvate converted to lactate, lactate dehydrogenase converts NADH to NAD+ to regenerate coenzyme and allow glycolysis to run.
What is the reversible change in gene expression in cancer cells that increases the glycolysis rates under hypoxic conditions?
PHDs (prolyl hydroxylases) hydroxylate HIF1a in the presence of oxygen, targeting it for degradation by VHL ligase.
In the absence of oxygen, there is no HIF1a inhibition, so HIF1a upregulates and drives glycolysis genes.
What are the irreversible changes in cancer cells that increases the glycolysis rates under hypoxic conditions?
- FH & SDH - Fumarate hydratase and succinate dehydrogenase are mutated in some tumours, causing the accumulation of fumarate and succinate (oncometabolites), impairing mitochondrial ATP synthesis and the TCA cycle.
Also inactivate PHDs to increase HIF1a levels. - Mutations in VHLs are found in some cancers. HIF1a can accumulate.
Why does glycolysis benefit a proliferating cell?
Glycolysis is insufficient, but fast.
Waste product is recycled by cori cycle in liver.
What is the PPP and how is this alternative metabolism pathway important for tumour growth and proliferation.
Pentose phosphate pathway
Diagram
Makes NADPH for the anabolic pathway and ROS protection. Also for nucleotide synthesis.
What is the function of PKM2 in cancer cells, and how is it regulated?
Shuttles more pyruvate into lactose than into the mitochondria. Increases intermediates available for the PPP and limits ROS production.
C-Myc (oncogene) is dysregulated in cancers and induces increased splicing factors which increases PKM2 expression.
What is the function of p53 in cancer cells and how is it regulated?
p53 suppresses glucose import, suppresses glycolysis and promotes PPP and mitochondrial respiration.
Mutations in p53 cause less mitochondrial respiration.
What therapies are being developed to target tumour metabolism?
1 - (2-deoxyglucose) blocks glucose uptake.
2 - MCT4 inhibitors block lactate export.
