Prostate cancer may be exploiting a surprising source of fuel to resist hormone therapy: the breakdown of dietary amino acids. In a preclinical study published in Nature Metabolism, researchers at Weill Cornell Medicine have identified a metabolic pathway that links the amino acids isoleucine and valine to cholesterol production, androgen signaling and the spread of prostate tumors. Their findings suggest that cancer cells can redirect ordinary nutrient-processing reactions into a biochemical survival program, allowing them to continue growing even after treatment suppresses the hormones they normally depend on.

The central player is propionyl-CoA, a molecule generated when cells break down certain branched-chain amino acids, particularly isoleucine and valine. These essential amino acids cannot be produced by the human body and are obtained through food, including meat, fish, dairy products and other protein-rich sources. Under normal conditions, propionyl-CoA is one intermediate in the metabolism of nutrients for energy and cellular construction. The Weill Cornell team found that, in prostate cancer, the molecule can also function as a signal that changes the behavior of a key regulatory protein.

The investigators began by examining human prostate tumors and discovered elevated levels of propionylcarnitine, a closely related metabolite that reflects propionyl-CoA activity. The metabolite was particularly abundant in more aggressive tumors, providing a clue that the pathway might be associated with disease progression. Further experiments in prostate cancer cells revealed that propionyl-CoA chemically modifies a protein called sterol regulatory element-binding protein 2, or SREBP2. This modification, known as propionylation, stabilizes SREBP2 and keeps it active for longer than it normally would be.

SREBP2 is a master regulator of cholesterol metabolism. In healthy cells, it operates as part of a feedback system: when cholesterol levels fall, SREBP2 enters the nucleus and activates genes involved in cholesterol synthesis and uptake. As cholesterol accumulates, the pathway is normally dampened, preventing excessive production. The new findings indicate that propionyl-CoA can interfere with this metabolic brake. By propionylating SREBP2, the cancer cell effectively keeps its cholesterol-making machinery switched on, even when internal cholesterol levels would ordinarily signal that production should stop.

That sustained cholesterol production may be especially valuable to prostate tumors because cholesterol is not merely a component of cell membranes. It can also serve as a precursor for steroid hormones, including androgens such as testosterone. Androgens activate the androgen receptor, a transcription factor that drives the expression of genes supporting prostate cancer growth and survival. Hormone therapies, including androgen-receptor inhibitors such as enzalutamide, are designed to disrupt this signaling system. However, if tumor cells increase their own supply of cholesterol and use it to generate additional male hormones, they may preserve enough androgen signaling to withstand treatment.

The researchers observed that propionyl-CoA levels increased when prostate cancer cells were deprived of male hormones in laboratory models. This suggests that hormone suppression itself may trigger the metabolic adaptation. Rather than simply becoming starved of a growth signal, the cancer cells appear capable of switching their nutrient-processing priorities, converting amino-acid breakdown into a route for restoring cholesterol and steroid production. The result is a feedback loop in which treatment-induced stress activates a pathway that helps rebuild the very hormonal environment therapy is intended to eliminate.

Experiments in mice provided additional evidence that this pathway can influence tumor behavior. Restricting isoleucine and valine slowed tumor growth and reduced the ability of prostate cancer cells to colonize the lungs. Conversely, increasing propionyl-CoA promoted tumor growth and enhanced lung colonization. These results do not establish that dietary manipulation can treat prostate cancer in people, but they suggest that nutrient availability may influence the metabolic flexibility that allows tumors to become more aggressive. The findings also point toward enzymes involved in converting isoleucine and valine into propionyl-CoA as possible drug targets.

The pathway could have implications beyond amino-acid metabolism. Because it ultimately drives cholesterol synthesis, it may help explain why studies of statins, cholesterol-lowering drugs, have produced mixed results in prostate cancer. If only a subset of tumors relies heavily on propionyl-CoA-driven SREBP2 activation, those tumors might be more vulnerable to interventions that block cholesterol production. Measuring metabolites such as propionylcarnitine, or assessing the activity of the associated enzymes and SREBP2 modification, could eventually help identify patients most likely to benefit from cholesterol-lowering strategies combined with hormone therapy.

The researchers caution that the biology is more complicated than simply removing two amino acids from the diet. Isoleucine and valine are required for normal protein synthesis and other physiological processes, while propionyl-CoA can arise from additional sources within the body. Aging, cancer-associated muscle wasting, obesity and diabetes can all alter amino-acid metabolism and circulating nutrient levels. Whether these systemic changes increase propionyl-CoA production inside human tumors remains unknown. Any dietary intervention would therefore require carefully controlled clinical studies to determine safety, nutritional consequences and whether it improves treatment responses.

The study underscores a growing view of cancer metabolism as a communication system rather than a passive source of energy. Nutrients and their breakdown products can act as molecular messages, changing gene regulation and helping malignant cells adapt to therapy. By connecting branched-chain amino acids to SREBP2, cholesterol production and androgen signaling, the Weill Cornell investigators have identified a potential explanation for how prostate tumors evade hormone deprivation. The next steps will be to test drugs that block the pathway, determine whether dietary strategies can safely influence it, and establish whether the mechanism operates in patients with treatment-resistant disease. If confirmed, a metabolic signal generated from ordinary nutrients could become a new vulnerability in one of the most persistent forms of cancer.

Subject of Research: Prostate cancer metabolism, hormone therapy resistance, branched-chain amino acids, propionyl-CoA, cholesterol synthesis and androgen signaling.

News Publication Date: 20-Aug-2026

Web References: https://mediasvc.eurekalert.org/Api/v1/Multimedia/5a01e294-78ba-4b60-93fd-2713d5b5ac91/Rendition/low-res/Content/Public; https://vivo.weill.cornell.edu/display/cwid-job2064; https://vivo.weill.cornell.edu/display/cwid-zhl4003

Image Credits: Zhongchi Li

Keywords: Prostate cancer, prostate tumors, hormone therapy, enzalutamide, androgen receptor, amino acid metabolism, isoleucine, valine, propionyl-CoA, propionylcarnitine, SREBP2, cholesterol metabolism, cancer metastasis, statins, metabolic therapy.

Tags: amino acid breakdown in cancerandrogen signaling pathwaysbiochemical survival mechanisms in hormone-resistant prostate cancerbranched-chain amino acids in tumor growthcholesterol biosynthesis in prostate cancerdietary amino acids and cancer progressionhormone therapy resistance in prostate cancermetabolic reprogramming in cancer cellsmetabolomics in prostate tumor analysisprostate cancer metabolismrole of propionyl-CoA in tumor survivaltargeting amino acid metabolism for cancer therapy