11- Cancer Metabolism

Question 1

How do cancer cells differ from normal cells in the way they metabolize glucose?

Answer 1

• 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

Question 2

What was the Warburg hypothesis (proven wrong)?

Answer 2

• 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

Question 3

If there is normal mitochondria in cancer cells, why do they metabolize glucose differently?

Answer 3

• 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

Question 4

What enhances the expression/ activity of glycolysis mediators?

Answer 4

• 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)

Question 5

What is HIF-1?

Answer 5

• 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

Question 6

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)

Answer 6

• 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

Question 7

What is biosynthesis?

Answer 7

• ↑ 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

Question 8

What are some limitations of aerobic glycolysis for biosynthesis?

(doubts if Warburg effect really ↑ biosynthesis)

Answer 8

• 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

Question 9

What is a non-cell intrinsic function of the Warburg effect?

• may be important for later stages of cancer progression
  (invasion/ metastasis)

Answer 9

• 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

Question 10

What are some cell-intrinsic tumor-promoting signalling promoted by glycolysis?

Answer 10

• glycolysis modulates ROS (↓ oxidative stress to prevent cell death)
• modulates chromatin state > promote transcription/ DNA repair
  > favors histone acetylation > opening of chromatin

Question 11

What is the link between glycolysis/ histone acetylation?

Answer 11

• glycolysis > lactate production > ↓ pH > ↑ histone acetylation
• inhibition of glycolysis > ↓ levels of lactate/ pyruvate