Abstract 2557: 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation

Abstract

Abstract Western-type diets have been increasingly enriched with linoleic acid (LA). The impact of excess dietary LA on cancer risk remains poorly understood although some studies suggest that high LA diets promote chemically-induced colorectal carcinogenesis (CRC) in rodent models. 15-lipoxygenase-1 (15-LOX-1), the main metabolizing enzyme of LA, is transcriptionally silenced during the early stages of CRC. Whether 15-LOX-1 impacts the effects of excess LA on CRC is unknown. Herein, we report that high dietary LA promoted CRC in intestinally targeted APC mutation (ApcΔ580) and azoxymethane-induced CRC mouse models by upregulating expression of LRP5, a Wnt receptor, and aberrant β-catenin activation. These effects were negatively regulated by 15-LOX-1 when this enzyme was transgenically expressed in intestinal epithelial cells. Complementary genetic deletion studies of 15-LOX-1 in mice further supported 15-LOX-1's suppressive effects on these events. Mechanistic studies showed that 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17 and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time the importance of linoleic acid metabolism by 15-LOX-1 within complex lipids such as PI3P in regulating LRP5 membranous abundance and subsequently Wnt/β-catenin aberrant signaling activation and CRC risk. These results strongly support the need to carefully consider the potential of increasing CRC risk by enriching the diets with LA especially for individuals with low 15-LOX-1 expression. Citation Format: Fuyao Liu, Xiangsheng Zuo, Yi Liu, Yasunori Deguchi, Micheline J. Moussalli, Weidong Chen, Peiying Yang, Bo Wei, Lin Tan, Philip L. Lorenzi, Shen Gao, Jonathan C. Jaoude, Amir Mehdizadeh, Lovie A. Valentin, Daoyan Wei, Imad Shureiqi. 15-lipoxygenase-1 suppresses linoleic acid promotion of colorectal tumorigenesis through oxidative metabolism of PI3P_linoleic acid to inhibit membranous LRP5 recycling and WNT/β-catenin signaling activation [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2557.