Reprogramming energy metabolism in cancer Christian Ludwig

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

What are the hallmarks of cancer?

And the new ones…

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

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

ATP – energy currency

http://www. sabiosciences http://www.sabiosciences.com/pathwaymagazine/minireview/metabolicre_programming.php

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

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

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…

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

PTEN activity lies downstream of many signalling pathways http://www.bioscience.org/2005/v10/af/1755/fulltext.php?bframe=figures.htm

AKT activation increases glucose uptake Yuan et al. Cell Res (2007) 17: 772-782 http://student.biology.arizona.edu/honors2003/group05/bg.html

AKT

p53 – a central metabolic regulator Vousden and Ryan. Nature Rev Cancer (2009). 9:691-700

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

p53 controls oxidative phosphorylation through SCO2

Oxidative phosphorylation p53 SCO2 Functional COX Leary et al. Hum Mol Genet (2004) 13:1839-1848

P53 deficient tumours therefore exhibit the Warburg Effect

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

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

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

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

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(633-637)

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

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

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

Both metabolites disrupt normal cell signalling processes Pollard and Ratcliffe. Science (2009) 324:192-194