altered energy production and intermediary metabolism of cancer cells

ATP output in oxidative phosphorylation vs aerobic glycolysis (Warburg effect)

• 36 vs 4 ATP

anabolic enzymes in citric acid cycle purpose

• can salvage intermediary metabolites for biosynthetic reactions resulting in nucleotides and lipids

warburg effect

• cancer cells even in abundnat oxygen have increased levels of lactic acid

• altered metabolism

FDG-PET imaging

• increases glucose uptake is exploited in FDG-PET imaging

• FDG is a radioactive glucose analogue and is very sensitive for the detection of metastases

glutaminolysis steps

1. deamination of glutamine → glutamate

2. conversion to alpha ketoglutarate through transaminases

3. enters TCA cycle

impact of glutaminolysis

• allows metabolites such as alanine, aspartate, citrate and glutamate to be replenished

• provides extra carbon and nitrogen for amino acids

advantages of warburg effect

• cancer cells better adapted to fluctuating oxygen

• metabolites can be redirected without affecting energy production

• reduction of ROS

• lactic acid can be used by cancer and stromal cells to regenerate pyruvate

• lactic acid can result in suppression of immune cells

lactic acid can be used for and result in

• lactic acid can be used by cancer and stromal cells to regenerate pyruvate

• lactic acid can result in suppression of immune cells

What causes the reprogramming of intermediary metabolism in cancer cells?

Oncoproteins and tumour suppressor proteins regulate the expression and/or activity of multiple enzymes that regulate metabolic flux

PKM2

• active isoform with exon 9

• undergoes oligomerisation

• catalyses final step of glycolysis

PKM in cancer cells

• PKM is overexpressed in cancers induced by Myc oncogene

• exists as low activity dimer instead of high activity tetramer

• glycolysis is slower so more metabolites can be used in other pathways

forced expression of PKM1 in malignant cells

• always tetrameric and active

• reverses Warburg effect

• blocks tumour formation

treating metabolic enzymes

• inhibitors of lactatate dehydrogenase - prevent fermentation

• block the phosphopentase pathway

• fatty acid synthase inhibitors

• glutaminolysis inhibitors

• ALL ASSOCIATED WITH TOXICITY SO NO BUENO

Gain of function of Myc effects on metabolism

• inc expression of genes which support anabolic growth

  • transporters and enzymes involved in glycolysis, fatty acid synthesis, glutaminolysis, serine metabolism and mitochondrial metabolism

how is HIF-1 activated?

• accumulation of ROS

• hyperactivation of mTORC1

• accumulation of the TCA cycle metabolites succinate or fumarate

induction of metabolic pathway which support tumorigenesis is achieved by

• deregulation of PI3K-AKT-mTOR signaling

• loss of tumour suppressors

• activation of oncogenes

how does glutamine provide acetyl-CoA?

• reductive carboxylation of alpha ketoglutarate to form citrate

• citrate is cleaved to yield acetyl-CoA and oxaloacetate

• happens under hypoxia or mitochondrial stress

how do cancer cells have diminished need for ATP

• decrease Na/K ATPase

• rise in ADP activates AMPK pathway

  • activation of catabolic pathways like fatty acid oxidation to stimulate ATP production

KEAP1

• tumour suppressor gene

• which is mutated in many lung cancers

• usually acts as a sensor for variety of chemical and environmental stresses such as carciongens in cigarettes smoke to ROS generated

  • KEAP1 will then encode cellular antioxidants and detoxification enzymes

  • also relied on transcription factor NRF2

what happens in different oxygen conditions with KEAP1

in absence of oxidative stress NRF2 is sequestered by KEAP1 for ubiquitylation and degradation

• this minimizes the antioxidant response

when there is oxidative stress then NRF2 is released

KEAP1 mutations in cancer

• inactivating KEAP1

• mutations to binding site of NRF2 gene