Abstract 1548: Deletion of peroxisomal 3-ketoacyl-CoA thiolase promoted overall survival in the KPC mice

Abstract Background: Fast-growing cancer cells obtained ATP from fatty acid oxidation (FAO). We found that medium-chain acyl-carnitines (MC-AC) were increased by carnitine acyl-carnitine carrier knockdown in pancreatic ductal adenocarcinoma. MC-AC can be produced only in the peroxisome. Therefore, we propose that ATP production in cancer cells may depend on the peroxisomal FAO in addition to mitochondrial FAO. Methods: We have tested whether peroxisomal FAO is reduced by knockdown of peroxisomal 3-ketoacyl-CoA thiolase (acetyl-CoA acyltransferase 1, ACAA1). We have examined effects on ATP level and tumor growth by ACAA1 knockdown in PDAC cells, and cancer survival by crossbreeding of KPC mice (KrasG12D/+; Trp53R172H/+; P48-Cre) and Acaa1+/- mice. Findings: Peroxisomal FAO target levels in PDAC patients are higher than in normal individuals. In in vitro experiments, ACAA1 knockdown in PDAC cells reduced 40% of ATP production. In in vivo experiments, xenograft mouse models using human PDAC cells with ACAA1 knockdown showed significantly reduced tumor formation. Crossbreeding of the KPC mice with Acaa1+/- mice significantly increased the survival rate. Interpretation: While normal cells rely on glucose oxidation, ATP production in PDAC cells is critically dependent on FAO in peroxisomes and mitochondria. This suggests that to achieve complete FAO inhibition in cancer, it is necessary to block FAO in both peroxisomes and mitochondria. Funding source: This research was supported by the Basic Science Research Program through the National Research Foundation of Korea (NRF), funded by the Ministry of Science and ICT to SK (NRF-2019M3A9G1104345) and by a grant from the National Cancer Center of Korea to SHS (NCC 24H1210-2) and JWC (NCC 2410892-2). Citation Format: Mingyu Kang, Woosol Hong, Woojin Ham, Chaeyoung Kim, Ho Lee, Sang Myung Woo, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Soo-Youl Kim. Deletion of peroxisomal 3-ketoacyl-CoA thiolase promoted overall survival in the KPC mice [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 1548.