11- Cancer Metabolism
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How do cancer cells differ from normal cells in the way they metabolize glucose?
• in normal differentiated cells > glucose metabolism depends on the presence of O2 (oxidative phosphorylation vs anaerobic glycolysis) • in aerobic conditions (O2) > glycolysis > Krebs cycle > 36 ATP • in anaerobic conditions (no or low O2) > glycolysis > generate lactate via fermentation > 2 ATP • cancer cells undergoing rapid proliferation preferentially use glycolysis/ generate lactate, even if there is O2 = Aerobic Glycolysis • common phenomenon in cancer cells called Warburg Effect > 4 ATP
What was the Warburg hypothesis (proven wrong)?
• since cancer cells do not respire but ferment, cancer is caused by damaged/ insufficient respiration • but cancer cells have normal mitochondria > capable of respiration, so hypothesis proven wrong
If there is normal mitochondria in cancer cells, why do they metabolize glucose differently?
• differential expression/ activity of metabolic mediators in cancer cells vs normal differentiated cells • GLUT1-4 overexpressed in cancer cells (glucose transporter) • glycolytic enzymes overexpressed in cancer cells (anaerobic glycolysis) • cytosolic/ mitochondria enzymes involved in fermentation/ respiration
What enhances the expression/ activity of glycolysis mediators?
• Hypoxia- organs existing blood supply is not sufficient to provide O2 to expanding tumor mass > upregulates HIF1-a • Overactivity of signalling pathways that promote survival/ rapid proliferation > upregulates HIF1-a • Loss of tumor suppressor genes (VHL/ p53) involved in O2 sensing mechanisms (HIF1-a is a key player)
What is HIF-1?
• Hypoxia Inducible Factor 1 > composed of 2 units (HIF1-a/ HIF1-b) • HIF1-b is always expressed/ HIF1-a expression regulated by O2 • HIF1a expression is key to cancer metabolism Normoxia > no HIF1-a (VHL binds to/ degrades it) Hypoxia > no degradation of HIF1-a
What would be an advantage for cancer cells of an energetically inefficient process (aerobic glycolysis)? (only 2-4 ATP compared to 36 ATP by Krebs cycle)
• rapid ATP synthesis (10-100 x faster) > way more efficient ATP production even though less per cycle • biosynthesis necessary for rapid proliferation • a cancer-promoting tumor microenvironment (↓ pH) • glycolytic shift activates cell-intrinsic tumor-promoting cell signalling
What is biosynthesis?
• ↑ glucose consumption via glycolysis generates excess metabolites/ carbon > used for de novo generation of nucleotides/ lipids/ proteins > building blocks of cells produced by rapid proliferation
What are some limitations of aerobic glycolysis for biosynthesis? (doubts if Warburg effect really ↑ biosynthesis)
• when lactate generated from glucose during aerobic glycolysis, there are several limitations for biosynthesis > most carbon not retained (excreted as lactate) no overall loss/ gain of NAD+/NADH
What is a non-cell intrinsic function of the Warburg effect? • may be important for later stages of cancer progression (invasion/ metastasis)
• lactate secretion ↓ pH in environment (acidic) > favors M2 phenotype in tumour-associated macrophages (TAM) > competition for glucose between cancer cells/ TILs favors cancer cells/ ↓ anti-tumor immune function
What are some cell-intrinsic tumor-promoting signalling promoted by glycolysis?
• glycolysis modulates ROS (↓ oxidative stress to prevent cell death) • modulates chromatin state > promote transcription/ DNA repair > favors histone acetylation > opening of chromatin
What is the link between glycolysis/ histone acetylation?
• glycolysis > lactate production > ↓ pH > ↑ histone acetylation • inhibition of glycolysis > ↓ levels of lactate/ pyruvate