Prostate tumors can rewire amino acid metabolism to override the normal brakes on cholesterol production, a process that may fuel hormone therapy resistance, according to a study by Weill Cornell Medicine investigators.

The preclinical study, published Aug. 20 in Nature Metabolism, revealed that propionyl-CoA, a compound produced by the breakdown of amino acids isoleucine and valine during normal energy metabolism, acts as a signal that switches on cholesterol production. This helps prostate cancer cells adapt to the hormone-deprived conditions resulting from treatment and acquire more aggressive features.

By revealing this previously unrecognized connection, the study identified a potential weakness in prostate cancer that could be targeted with new drugs or, pending clinical testing, dietary strategies that reduce levels of isoleucine and valine. These essential amino acids are abundant in protein-rich foods such as meat, fish and dairy products.

“Our study uncovers an unexpected way prostate cancer cells can adapt when hormone signaling is blocked,” said senior author John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research and professor of pharmacology at Weill Cornell. “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.”

The study’s lead author, Zhongchi Li, an instructor in pharmacology at Weill Cornell, explained that the team identified elevated levels of propionylcarnitine, a metabolite closely related to propionyl-CoA, in more aggressive human prostate tumors. 

Following this clue, the researchers discovered that propionyl-CoA promotes the addition of a chemical tag, called propionylation, to a protein named SREBP2. This tag stabilizes SREBP2 and keeps cholesterol-producing genes switched on.

Normally, SREBP2 acts as a sensor that boosts cholesterol production when cholesterol levels are low and reduces production when levels are high, maintaining balance. However, propionyl-CoA enabled SREBP2 to remain active even under conditions that would normally suppress cholesterol production, allowing cancer cells to bypass this metabolic safeguard.

Prostate cancer cells use the excess cholesterol to produce androgens (testosterone and related male hormones), which activate the androgen receptor, a key driver of prostate cancer growth. Drugs like enzalutamide are designed to block this signaling pathway, but increased production of male sex hormones helps tumors maintain that signaling and become less responsive to treatment.

The researchers also found that propionyl-CoA levels rose when prostate cancer cells were deprived of male hormones in laboratory models, indicating that tumors may activate this pathway as a survival strategy when hormone signaling is disrupted by treatment.

“Because this pathway connects nutrients, cholesterol and hormone signaling, it gives us several points where we may be able to intervene,” Blenis said. “The long-term goal is to determine whether drugs or carefully controlled dietary strategies can make existing treatments work better.”

Though people normally get isoleucine and valine from their diet, other potential sources of propionyl-CoA exist in the body. Aging and cancer-associated cachexia can involve substantial muscle loss, while obesity and diabetes have been associated with altered circulating levels of branched-chain amino acids. Whether these systemic changes increase propionyl-CoA production within tumors remains unknown.

The researchers found that restricting isoleucine and valine slowed tumor growth and reduced metastases of prostate cancer cells to the lungs in mouse models. On the other hand, boosting propionyl-CoA levels promoted tumor growth and increased lung colonization. 

“If future clinical studies show that reducing valine and isoleucine in a patient’s diet is safe and effective, combining this approach with enzalutamide might improve the response to treatment,” Blenis said. “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.”

Because the pathway ultimately drives cholesterol production, the findings may also help explain why some studies show that cholesterol-lowering drugs known as statins appear to benefit some prostate cancer patients but not others. If validated in future studies, activity of this pathway may indicate which patients with prostate cancer would benefit from statins, Li said.

Blenis’ lab will continue to study the role of this pathway in other types of cancer, as well as in aging and metabolic diseases. 

“Metabolism does much more than supply energy and building blocks – it also generates signals that can change how cells behave,” Li said. “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.”

Bridget Kuehn is a freelance writer for Weill Cornell Medicine.