Lecture 17: Cancer and metabolism

Question 1

What is the Warburg effect?

Answer 1

Cancer cells produce atp via glycolysis, even when oxygen is available, turning glucose to lactate

Question 2

How and why are cancer cells inefficient?

Answer 2

How?
1. Inefficient ATP production
2. Ineffective use of glutamine (most common AA used for
generation of other AAs and nucleotides)
3. Cancer cells secrete a lot of glutamine-derived C and N as waste
rather than incorporation into macromolecules

Why?
1. Warburg proposed cancers cells have defective mitochondria
impairing respiration

Question 3

What are the advantages of this abnormal tumour metabolism for tumours?

Answer 3

Gives cancer cells a ready supply of building blocks for macromolecule synthesis

Allows cancer cells to take more than their share of nutrients, starving neighbours, gaining space for growth

Increases production of ROS (reative oxygen species) which can inactivate growth inhibitory enzymes such as phosphatases and enhance mutation rate by DNA damage

Question 4

Why is ROS balance important?

Answer 4

Low levels = support proliferation
High levels = detrimental, causing damage and death

High proliferation rates -> high ROS production, but cancer cells adapt to moderate ROS levels

Question 5

What is Hypoxia inducible factor?

Answer 5

(HIF) - transcription factor that controls the expression of many important genes (both metabolism and angiogenesis)

HIF activity is controlled by oxygen

HIF cooperaties with c-Myc in controlling the expression of glucose transporters and glycolytic enzymes

HIF AND MYC STIMULATE EXPRESSION OF MOST ENZYMES INVOLVED IN GLYCOLYSIS

HIF also inhibits mitochrondiral respiration by inducing pyruvate dehydrogenase kinase-1, which phosphoryates and inactivates pyruvate dehyrdogenase - key enzyme for conversion of pyruvate to acetyl-CoA

Question 6

What is tumour suppressor LKB1 and how is it involved in controlling the cells ATP energy status

Answer 6

1. Normal starved cells with dropped ATP detect increased AMP, which binds to AMP-activated protein kinase (AMPK), allowing the serine/Threonine kinase LKB1 to phosphorylate it
2. AMPK phosphorylates and inactivates a number of targets to improve the “energy chage” in the cells, switching off clycolysis and enhancing respiration/TCA cycle
3. Loss of LKB1 = uncoupling of glycolysis and TCA cycle

Question 7

What is tumour suppressor LKB1 and how is it involved in controlling the cells ATP energy status

Answer 7

1. Normal starved cells with dropped ATP detect increased AMP, which binds to AMP-activated protein kinase (AMPK), allowing the serine/Threonine kinase LKB1 to phosphorylate it
2. AMPK phosphorylates and inactivates a number of targets to improve the “energy chage” in the cells, switching off clycolysis and enhancing respiration/TCA cycle
3. Loss of LKB1 = uncoupling of glycolysis and TCA cycle

Question 8

How is pyruvate kinase involved?

Answer 8

PK catalysis the rate-limiting ATP-generating step of glycolysis, conversion of PEP to pyruvate.

Isoform PKM2 is found at high levels in cancer cells but is v inefficient. This helps accumulation f intermediates for biosynthesis and cuts down acetyl-CoA flux