altered energy production and intermediary metabolism of cancer cells

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

• 36 vs 4 ATP

which healthy cells have similar metabolic features to cancer cells?

• any cells undergoing aerobic glycolysis

• T cells

• normal stem cells

• fibroblasts

how does the shared metabolism of cancer cells with other cells compromise targeting cancer cell metabolism?

• most therapeutics which target the aerobic glycolysis pathway are toxic

• dehydrogenase inhibitors, fatty acid synthase inhibitors

• need t cell, stem cells and fibroblasts to combat infection, allow growth and replacement of cells, and for wound repair

what strategies can be used to explore therapeutic vulnerabilities created through metabolic wiring of cancer cells

• plasmax

• AI and CRISPRR

• allow modulation of tumour microenvironment, induction of cell death pathways

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

PKM-1

• 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

  • PKM1 → PKM2

• 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 from metabolic cycles?

• 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?

• glutamine → glutamate → alpha ketoglutarate (glutaminolysis)

• 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

regulation of oxidative stress

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 and impact

• inactivating KEAP1

• mutations to binding site of NRF2 gene

• allows cancer cells to survive as no sensitivity through KEAP1