1. Reprogramming energy metabolism in cancer
Christian Ludwig

2. Learning Outcomes
Understand that changes in cancer cell phenotype require altered metabolism
Be able to describe how mutations associated with cancer directly and indirectly alter cell metabolism
Be able to give examples of metabolic enzymes mutated in cancer and their role in oncogenesis

3. What are the hallmarks of cancer?

4. And the new ones…

5. Metabolic transformation is required to permit cancer hallmarks
New phenotype required
Metabolic implications?
Self-sufficiency in growth signals
Proliferation
New proteins, DNA, RNA and ATP
Insensitivity to anti-growth signals
See above
Sustained angiogenesis
New endothelial cell proliferation, survival in hypoxia
Glycolytic ATP generation, new proteins, DNA
Tissue invasion and metastasis
Cell movement, production of MMPs
New proteins, ATP
Evasion of apoptosis
Change in mitochondrial phenotype
Alterations in mitochondrial metabolic pathways
Replicative immortality
Ability to replicate indefinitely

6. Nutrients DNA, proteins, cell membranes. Energy. Proteins, DNA.

7. ATP – energy currency

8. http://www. sabiosciences

9. Energy versus macromolecules
- 2 ATP
Diverting carbons to macromolecule biosynthesis sacrifices ATP production

10. The Warburg Effect
The Warburg Effect describes an increased lactate production by cells under aerobic conditions
Misunderstandings about Warburg:
Warburg Effect can never be observed in hypoxia
It does not necessarily describe increased aerobic glycolysis, which is not unique to cancer cells

11. So why is the Warburg effect always talked about?
We observe increased lactate production in cancer cells and in most tumours
It is an indicator of metabolic transformation of tumour cells, but there are a number of different ways of getting this effect…

12. How does the Warburg Effect, and other transformed metabolic phenotypes occur?
Oncogene/tumour suppressor gene-induced changes in proliferative drive, and direct modulation of metabolism
Examples covered
PTEN
TP53
K-Ras
c-Myc

13. PTEN activity lies downstream of many signalling pathways

14. AKT activation increases glucose uptake
Yuan et al. Cell Res (2007) 17:

15. AKT

16. p53 – a central metabolic regulator
Vousden and Ryan. Nature Rev Cancer (2009). 9:

17. Vousden and Ryan. Nature Rev Cancer (2009). 9:691-700

18. p53 controls oxidative phosphorylation through SCO2

19. Oxidative phosphorylation p53 SCO2 Functional COX
Leary et al. Hum Mol Genet (2004) 13:

20. P53 deficient tumours therefore exhibit the Warburg Effect

21. What happens if TP53 is mutated instead of knocked out?
Retention of its ability to upregulate enzymes involved in:
Detox oxidative stress
DNA/RNA synthesis
Oxidative ATP generation
Increased glucose consumption

22. c-Myc transforms glutamine metabolism
Myc amplification often observed in tumours
Increases expression of Myc target genes
Dang, C.V. CSH Symposia (2011) 76:369-74

23. Why is c-Myc amplification so good at driving proliferation?

25. The metabolic phenotype of a tumour depends on the combination of mutations

26. K-Ras mutations transform the food source!
K-Ras V12 induces tumour cells to increase uptake of external protein
This can then be used to directly generate new proteins, ATP and DNA/RNA
Comisso et al. Nature (2013). 497( )

27. Pancreatic cancer – both TP53 and K-RAS mutations
K-RAS mutations provide increased glycolysis through AKT activation
Also increase ability to scavenge extra food from the environment
TP53 mutations increase anabolism and protection against oxidative stress and other toxins

28. Familial cancer syndromes illustrate role of metabolism in cancer
Succinate dehydrogenase
Paraganglioma and pheochromocytoma
Fumarate hydratase
Leiomyoma and renal cell carcinoma
Brookes et al. AJP Cell Physiol (2004) 287:C817-C833

29. Gottlieb and Tomlinson. Nature Rev Cancer (2005) 5:857-66

30. Both metabolites disrupt normal cell signalling processes
Pollard and Ratcliffe. Science (2009) 324: