Researchers at Weill Cornell Medicine have identified a metabolic process that may help explain why some prostate cancers become resistant to hormone therapy, pointing to possible new drug targets and even dietary strategies that could improve treatment in the future.
The preclinical study found prostate cancer cells can rewire the way they process certain amino acids, allowing tumors to keep producing cholesterol and male hormones even when treatment is designed to shut that system down.
The research, published Aug. 20 in Nature Metabolism, centers on a compound called propionyl-CoA, which is produced when the body breaks down the essential amino acids isoleucine and valine.
Researchers found that propionyl-CoA can effectively override the normal controls on cholesterol production inside prostate cancer cells. That matters because tumors can use excess cholesterol to produce androgens, including testosterone and related hormones that drive prostate cancer growth.
Hormone therapies such as enzalutamide are designed to block androgen signaling. But if tumors can continue producing androgens internally, they may be able to maintain that signaling and become less responsive to treatment.
“Our study uncovers an unexpected way prostate cancer cells can adapt when hormone signaling is blocked,” said John Blenis, senior author of the study and a professor of pharmacology at Weill Cornell Medicine. “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.”
Researchers trace the pathway
The team began by identifying elevated levels of propionylcarnitine, a metabolite related to propionyl-CoA, in more aggressive human prostate tumors.
Researchers then found that propionyl-CoA affects a protein called SREBP2, which normally regulates cholesterol production.
Under ordinary conditions, SREBP2 helps maintain balance by increasing cholesterol production when levels are low and reducing production when levels are high. The study found propionyl-CoA can add a chemical tag to SREBP2 through a process called propionylation.
That tag stabilizes the protein and keeps cholesterol-producing genes active even when the cell would normally shut them down.
In laboratory models, propionyl-CoA levels also increased when prostate cancer cells were deprived of male hormones, suggesting tumors may activate the pathway as a survival mechanism when hormone therapy interrupts normal androgen signaling.
“Because this pathway connects nutrients, cholesterol and hormone signaling, it gives us several points where we may be able to intervene,” Blenis said.
Dietary changes are one possible avenue
The findings also raise questions about whether reducing certain amino acids could make prostate cancer treatments more effective.
Isoleucine and valine are essential amino acids that people get through food and are common in protein-rich products including meat, fish and dairy.
In mouse models, researchers found restricting those amino acids slowed tumor growth and reduced the spread of prostate cancer cells to the lungs.
Increasing propionyl-CoA had the opposite effect, promoting tumor growth and increasing lung colonization.
That does not mean prostate cancer patients should begin restricting protein or specific amino acids on their own. The research remains preclinical, and investigators said clinical studies would be needed to determine whether dietary changes are safe or effective in humans.
If future studies support the approach, researchers said carefully controlled reductions in valine and isoleucine could potentially be combined with existing treatments such as enzalutamide.
Another possibility is developing drugs that block the enzymes prostate cancer cells use to convert those amino acids into propionyl-CoA.
Findings could also shed light on statins
Because the newly identified pathway ultimately increases cholesterol production, the findings may also help researchers better understand why cholesterol-lowering statin drugs appear to help some prostate cancer patients but not others.
If future studies confirm the connection, activity within the pathway could potentially be used to identify patients most likely to benefit from statin treatment.
Researchers are also interested in whether other changes in the body could feed the same process.
Aging and cancer-associated cachexia can cause substantial muscle loss, while obesity and diabetes have been linked to changes in circulating branched-chain amino acids. Whether those conditions increase propionyl-CoA production inside tumors remains unknown.
The Weill Cornell team plans to continue studying the pathway in prostate cancer, other cancers and metabolic diseases.
For now, the findings provide a new explanation for how prostate tumors may adapt under treatment pressure and offer several potential points for future therapies to target.
“Metabolism does much more than supply energy and building blocks — it also generates signals that can change how cells behave,” lead author Zhongchi Li said. “This study shows how one such signal can help cancer cells adapt to treatment.”
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