eBook Chapter 8 - Energy Metabolism in Cancer

Question 1

Describe the major differences between normal cell metabolism and cancer cell metabolism

Answer 1

Normal cells
- aerobic conditions –> use glycolysis to give pyruvate which enters TCA to produce CO2
- effective production of ATP and of metabolites for biosynthesis
- anaerobic conditions –> glycolysis is favoured to TCA
- in normal cells, glycolysis is a preferred way of processing glucose only in conditions of limited oxygen supply
Cancer cells
- switch to glycolysis even in aerobic conditions
- aerobic glycolysis allows the diversion of metabolites into various biosynthetic pathways required for active cell proliferation
- now its known that sustained aerobic glycolysis is linked to activation of oncogenes and/or loss of tumour suppressor genes

Question 2

Describe the features of glycolysis

Answer 2

• 2 moles ATP/mole glucose e
• very fast
• required for anabolic precursors
• can only use glucose
• oxygen independent

Question 3

Describe the features of the TCA cycle

Answer 3

• 36 moles ATP/mole glucose
• highly efficiency
• slower than glycolysis
• can use many substrates
• oxygen dependent

Question 4

How to cancer cells compensate for lower efficiency of glycolysis?

Answer 4

• increase glucose uptake by up regulating glucose transporters such as GLUT1/2/3/4
• elevate expression of glycolytic enzymes, often due to elevated transcriptional activity of oncogenes such as c-myc and HIF-1a

Question 5

How does PTEN influence metabolism

Answer 5

• tumour suppressor gene, normally negatively regulates loops PI-3-kinase –> PDK1 –> PDK2 –> Akt pathway
• Akt a central metabolic regulator activated in many tumours

Question 6

What affect does a K-Ras mutation have?

Answer 6

• may independently contribute to the reprogramming of cancer cells by transforming the food source
• ## K-Ras V12 induces tumours cells to increase uptake of external protein by macropinocytosis, this is true can be used directly to generate new proteins, ATP and DNA/RNA

Question 7

How does p53 affect metabolism?

Answer 7

• p53 suppresses glucose uptake by inhibiting transcription of Glut1 and Glut 4 and suppressing Glut3 expressing by blocking Nf-kB activation
• p53 controls oxidative phosphorylation through SCO2.

Question 8

What is the effect of knocking out p53?

Answer 8

• The cycle is non-functional and we see Warburg effect

Question 9

What is the effect of p53 being mutated instead of knocked out?

Answer 9

Often retains ability to upregulate enzymes involved in:

• detox oxidative stress
• DNA/RNA synthesis
• oxidative ATP generation
• increased glucose consumption

Question 10

What does c-Myc have do to with metabolism?

Answer 10

• many tumours which on glutaminolysis - a series of biochemical reactions processing glutamate
• upregualtion in tumours induced by c-Myc
• as c-Myc is often amplified in many cancers
• fuels TCA cycle, the intermediates which may, in turn, contribute to biosynthesis of a number of essential metabolites

Question 11

What are the effects of mutations in the TCA cycle?

Answer 11

Familial cancer syndromes

• functionality of TCA cycle is disrupted leading to elevation of hypoxia inducible factors which can be pro-oncogenic
• abnormal tumour microenvironment plays a major role in determining metabolic phenotype of cancer cells. it is characterised by poor blood perfusion, hypoxia and nutrient limitations.
• hypoxia stabilises HIF1 and HIF2 and allows activate of transcriptional programme which increases glycolytic capacity and decreases mitchondrial respiration
• HIFs are drivers of metabolic transformation, HIF1 can also be activated under normoxic conditions by the cinco-gene driven pathways e.g. PI3K