Hormone therapy is a mainstay of prostate cancer treatment, but tumours often find ways around it. A preclinical study in Nature Metabolism from the laboratory of John Blenis at Weill Cornell Medicine identifies one such escape route: tumours rewire how they break down the amino acids isoleucine and valine, generating a compound called propionyl-CoA that switches cholesterol production back on when it should be shut off.
The mechanism runs through SREBP2, the protein that normally regulates cholesterol levels. Propionyl-CoA drives a chemical modification, propionylation, that stabilises SREBP2 and keeps cholesterol-producing genes active. Cancer cells then convert the surplus cholesterol into androgens, the very hormones that drugs such as enzalutamide are designed to starve them of. Notably, propionyl-CoA levels rose when prostate cancer cells were deprived of male hormones, suggesting tumours deploy the pathway as a survival strategy under treatment.
The findings carried into living models and human samples. In mice, restricting dietary isoleucine and valine slowed tumour growth and reduced spread of prostate cancer cells to the lungs, while boosting propionyl-CoA did the opposite. Elevated levels of a related metabolite, propionylcarnitine, marked more aggressive human tumours. The authors suggest enzyme inhibitors or dietary strategies might one day complement hormone therapy, and that the pathway could help explain why cholesterol-lowering statins appear to help only some patients.