Propionyl-CoA Drives Cholesterol Production and Hormone Therapy Resistance in Prostate Cancer, Weill Cornell Study Finds
核心洞察
Weill Cornell Medicine researchers found that propionyl-CoA, a byproduct of isoleucine and valine breakdown, switches on cholesterol production in prostate cancer (搜索) cells.
The metabolite propionylates and stabilizes SREBP2 (搜索), keeping cholesterol-producing genes active even when cholesterol levels should suppress them.
Restricting isoleucine and valine slowed tumor growth and reduced lung metastases in mouse models, while boosting propionyl-CoA had the opposite effect.
Prostate tumors can rewire amino acid metabolism to override the normal brakes on cholesterol production, a process that may fuel resistance to hormone therapy, according to a preclinical study from Weill Cornell Medicine investigators published Aug. 20 in Nature Metabolism.
The work identifies propionyl-CoA — a compound generated when the essential amino acids isoleucine and valine are broken down during normal energy metabolism — as a signal that switches on cholesterol production. This allows prostate cancer (搜索) cells to adapt to the hormone-deprived conditions created by treatment and to acquire more aggressive features.
"Our study uncovers an unexpected way prostate cancer (搜索) cells can adapt when hormone signaling is blocked," said senior author Dr. John Blenis, the Anna-Maria and Stephen Kellen Professor in Cancer Research and 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."
A Metabolic Clue From Aggressive Tumors
Lead author Dr. Zhongchi Li, an instructor in pharmacology at Weill Cornell, said the team first identified elevated levels of propionylcarnitine, a metabolite closely related to propionyl-CoA, in more aggressive human prostate tumors. Following that clue, the researchers discovered that propionyl-CoA promotes the addition of a chemical tag, called propionylation, to a protein named SREBP2 (搜索). This tag stabilizes SREBP2 and keeps cholesterol-producing genes switched on.
Normally, SREBP2 (搜索) acts as a sensor that boosts cholesterol production when cholesterol levels are low and reduces production when levels are high, maintaining balance. Propionyl-CoA enabled SREBP2 to remain active even under conditions that would normally suppress cholesterol production, allowing cancer cells to bypass this metabolic safeguard.
The consequence is directly relevant to androgen-driven disease: prostate cancer (搜索) cells use excess cholesterol to produce androgens such as testosterone and related male hormones, which activate the androgen receptor (搜索), 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.
Hormone Deprivation Strengthens the Pathway
The pathway became more active under the very conditions created by hormone treatment. In laboratory models, propionyl-CoA levels rose when prostate cancer (搜索) cells were deprived of male hormones, indicating that tumors may activate this route as a survival strategy when hormone signaling is disrupted by therapy.
"Because this pathway connects nutrients, cholesterol and hormone signaling, it gives us several points where we may be able to intervene," Dr. Blenis said. "The long-term goal is to determine whether drugs or carefully controlled dietary strategies can make existing treatments work better."
Diet is one source of isoleucine and valine, both of which are abundant in protein-rich foods such as meat, fish and dairy products. However, 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 noted.
Amino Acid Restriction Slowed Tumors in Mice
The investigators next tested whether changing the availability of isoleucine and valine could affect disease in mouse models. Restricting the two amino acids slowed prostate tumor growth and reduced metastases of prostate cancer (搜索) cells to the lungs. Boosting propionyl-CoA levels had the opposite effect, promoting tumor growth and increasing 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," Dr. 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 (搜索) targeting therapies."
Implications for Statin Response
Because the pathway ultimately drives cholesterol production, the findings may also help explain why some studies show that cholesterol-lowering drugs known as statins (搜索) appear to benefit some prostate cancer (搜索) patients but not others. Dr. Li said that if validated in future studies, activity of this pathway may indicate which patients with prostate cancer would benefit from statins.
Dr. Blenis' laboratory 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," Dr. 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."
The study, titled "Isoleucine and valine promote prostate cancer (搜索) progression via propionyl-CoA-mediated cholesterol metabolism," was supported by the National Cancer Institute, the National Institute on Aging and the National Institute of Diabetes and Digestive and Kidney Diseases, all part of the National Institutes of Health, through grant numbers R01CA273357, R01CA301410, R01CA46595, DK135816, CA299862, AI172027, DK132244 and R01CA297829.