Researchers at Weill Cornell Medicine have identified a previously unknown link between amino acid metabolism and prostate cancer’s resistance to hormone therapy. Published in Nature Metabolism, the preclinical study found that prostate cancer cells can hijack the metabolism of two amino acids to boost cholesterol production, helping tumors become resistant to standard treatment.
“Our study uncovers an unexpected way prostate cancer cells can adapt when hormone signaling is blocked,” said John Blenis, PhD, professor of cancer research and pharmacology at Weill Cornell Medical College. “It raises the possibility that the availability of certain amino acids, whether from diet or altered metabolism, may affect how tumors progress and respond to therapy.”
Blenis and colleagues found elevated levels of propionylcarnitine in more aggressive prostate tumors. This metabolite is closely related to propionyl-CoA, a compound naturally produced when the amino acids isoleucine and valine are broken down.
In preclinical models, the researchers found that propionyl-CoA acts on SREBP2, a protein that normally regulates cholesterol production, switching it on when cholesterol levels are low and turning it off when levels are high. Proppionyl-CoA disrupts this metabolic safeguard, keeping SREPB2 active and allowing cancer cells to continue producing cholesterol.
Prostate cancer cells can then use the excess cholesterol to produce androgen hormones and activate the androgen receptor—a key driver of prostate cancer growth and the target of standard hormone therapy for prostate cancer. This allows tumors to maintain androgen signaling and become less responsive to treatment.
“Metabolism does much more than supply energy and building blocks—it also generates signals that can change how cells behave,” said Zhongchi Li, PhD, instructor in pharmacology at Weill Cornell Medical College. “This study shows how one such signal can help cancer cells adapt to treatment, highlighting why the connections between diet, metabolism, and therapy deserve closer attention.”
The study also showed that propionyl-CoA levels rose when prostate cancer cells were deprived of androgens, suggesting that tumors may activate this pathway as a survival strategy in response to hormone therapy. In mouse models, the researchers found that restricting isoleucine and valine slowed down tumor growth and reduced metastases of prostate cancer to the lungs. Conversely, boosting propionyl-CoA levels promoted tumor growth and metastasis.
Isoleucine and valine are particularly abundant in protein-rich foods such as meat, fish, and dairy. Propionyl-CoA can also potentially be produced as a result of muscle loss from aging and cachexia, a common cancer complication. Obesity and diabetes have also been associated with altered circulating levels of certain amino acids. However, it remains unknown whether these conditions can increase propionyl-CoA production within tumors.
“If future clinical studies show that reducing valine and isoleucine in a patient’s diet is safe and effective, combining this approach with enzalutamide [hormone therapy] might improve the response to treatment,” said Blenis. “In addition, drugs that inhibit key enzymes required to convert isoleucine and valine into propionyl-CoA could aid in limiting resistance to androgen receptor targeting therapies.”
These findings also point to a potential explanation for why statins, widely used to lower cholesterol levels, appear to benefit some prostate cancer patients but not others. Because the pathway identified in the study is involved in cholesterol production, measuring its activity could potentially help identify which patients are most likely to benefit from statins.
“Because this pathway connects nutrients, cholesterol, and hormone signaling, it gives us several points where we may be able to intervene,” said Blenis. “The long-term goal is to determine whether drugs or carefully controlled dietary strategies can make existing treatments work better.”
