Hypoxia compound disrupts cancer cell metabolism

Researchers have discovered that a compound used to study the effects of oxygen deprivation disrupts a key pathway in cancer cell metabolism, critical for tumours to grow and survive.

The study, led by researchers at the Crick and their GSK collaborators, reveals a new mode of action for the compound – known as DMOG – and could help researchers develop new cancer treatments that target cancer metabolism, in the future.

“We were surprised to find in the lab that DMOG caused some types of breast cancer cells to die, but not others,” says Louise Fets, postdoc at the Crick and first-author of the paper. This effect was independent of the known effects of DMOG on oxygen-dependent signalling.

“So we started looking at what DMOG was doing inside these cells and why there was variability in their response to this compound,” she says.

Further analysis revealed that sensitivity to DMOG correlated with the presence of a specific protein transporter on the membrane of cancer cells, known as MCT2. Breast cancer cells with high MCT2 expression were killed by DMOG, whereas cells with low expression survived.

The team discovered that MCT2 transports a derivative of DMOG inside cancer cells, where it disrupts multiple enzymes in glutamine metabolism – an essential amino acid for cancer cell survival. 

The findings, published in Nature Chemical Biology suggest that MCT2 expression could be used to predict which cancers are likely to respond to DMOG, or similar compounds.

“DMOG has classically been used to mimic the body’s reaction to low oxygen conditions, and it’s exciting to start investigating this compound in the context of cancer metabolism,” says Dimitrios Anastasiou, group leader at the Crick and corresponding author of the paper.

“This fruitful collaboration with the GSK-Crick LinkLabs has given us real insight into the mechanism of action of DMOG in cancer cells, and could help us design similar-compounds to target MCT2-positive cancers in the future.”