Abstract 4302: Loss of carnitine acyl-carnitine carrier induced tumor regression by mTOR inactivation

Purpose: We found that most ATP production in cancer cells depends on fatty acid oxidation (FAO). However, the direct link between FAO and cancer promotion has not been interpreted. Therefore, we propose that blocking FAO in cancer may prevent pancreatic cancer growth promotion by blocking its ATP production. Experimental Design: To block FAO, CAC (carnitine-acylcarnitine carrier, gene: SLC25A20) in the mitochondria inner membrane was knocked down in cancer cells, which was implanted for xenograft in mice. To compare cancer development, survival rates and histopathological differences were analyzed with KPC mice (KrasG12D/+; Trp53R172H/+; Pdx1-Cre) and KPC/Cac+/- mice. Results: By CAC knockdown, the cancer cells reduced ATP production and decreased cell growth. Proteomic analysis showed that CAC knockdown significantly reduced cancer cell growth following mTOR inactivation by reduced ATP production, consequently leading to cell death. Xenografts using CAC knockdown PDAC cells showed up to 80% decrease of tumor growth compared to the control. Furthermore, the median survival of KPC/Cac+/- mice was increased by 3.1 weeks compared to KPC mice. Conclusion: Blocking FAO by CAC knockdown significantly suppressed tumor growth by mTOR inactivation through ATP depletion in pancreatic cancer cells. mTOR inactivation by CAC knockdown, consequently, decreased levels of cyclin D and PARP, which were followed by cell cycle arrest and cell death. Thus, even if signal transduction is induced by various growth receptors, mTOR cannot be activated when ATP levels fall below the Km value. 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 WC (NCC 2410891-1) and JWC (NCC 2410892-2). Citation Format: Joon Hee Kang, Ho Lee, Sang Myung Woo, Wonyoung Choi, Sung Hoon Sim, Jung Won Chun, Soo-Youl Kim. Loss of carnitine acyl-carnitine carrier induced tumor regression by mTOR inactivation [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 4302.