Abstract 3802: Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism

Abstract Enhanced cholesterol synthesis and storage in lipid droplets are strongly associated with cancer aggressiveness, particularly in lipid-rich and hormone-sensitive cancers such as prostate cancer. While tumor cells tightly regulate cholesterol anabolism and catabolism in response to nutrient states, the mechanisms that sense nutrient status and drive these processes remain poorly understood. Emerging evidence highlights mitochondria as key hubs of signal transduction, with mitochondrial metabolites serving as pivotal signaling molecules. Our prior work identified that the propionate metabolism pathway is remodeled during metastasis, with metabolites from this pathway acting as signaling regulators. Notably, patient data reveal that elevated propionyl-carnitine levels in prostate tumor tissues correlate with increased tumor aggressiveness. To investigate the role of propionyl-CoA in prostate cancer progression, we manipulated its levels in prostate cancer cells and assessed its effects on proliferation, colonization, and lipid metabolism both in vitro and in vivo. We discovered that mitochondrial metabolism of branched-chain amino acids (BCAAs), specifically isoleucine and valine, is a major source of cellular propionyl-CoA. This metabolite drives the propionylation of sterol regulatory element-binding protein 2 (SREBP2), promoting cholesterol synthesis and storage. The accumulated cholesterol fuels steroidogenesis, facilitating prostate tumor growth, colonization, and therapeutic resistance. Our findings establish a direct link between amino acid metabolism and cholesterol anabolism, unveiling a novel mechanism of cholesterol regulation in prostate cancer progression. This study highlights the therapeutic potential of targeting propionyl-CoA production, particularly through the metabolism of isoleucine and valine, to disrupt cholesterol synthesis and combat prostate cancer progression. Citation Format: Zhongchi Li, Shuchen Liu, Olivia Kester, Wenbing Jin, Un In Chan, Zhucui Li, Nayah Bullen, John Blenis. Isoleucine and valine promote prostate cancer progression via propionyl-CoA-mediated cholesterol metabolism [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 3802.