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Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P.
Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P.
- Source :
- Cell Reports; Aug2020, Vol. 32 Issue 7, pN.PAG-N.PAG, 1p
- Publication Year :
- 2020
-
Abstract
- APC mutation activation of Wnt/β-catenin drives initiation of colorectal carcinogenesis (CRC). Additional factors potentiate β-catenin activation to promote CRC. Western diets are enriched in linoleic acid (LA); LA-enriched diets promote chemically induced CRC in rodents. 15-Lipoxygenase-1 (15-LOX-1), the main LA-metabolizing enzyme, is transcriptionally silenced during CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling is unclear. We report that high dietary LA promotes CRC in mice treated with azoxymethane or with an intestinally targeted Apc mutation (Apc <superscript> Δ580 </superscript>) by upregulating Wnt receptor LRP5 protein expression and β-catenin activation. 15-LOX-1 transgenic expression in mouse intestinal epithelial cells suppresses LRP5 protein expression, β-catenin activation, and CRC. 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) leads to PI3P_13-HODE formation, which decreases PI3P binding to SNX17 and LRP5 and inhibits LRP5 recycling from endosomes to the plasma membrane, thereby increasing LRP5 lysosomal degradation. This regulatory mechanism of LRP5/Wnt/β-catenin signaling could be therapeutically targeted to suppress CRC. • Colonic 15-LOX-1 expression inhibits colon cancer promotion by linoleic acid in mice • Dietary linoleic acid upregulates LRP5 to enhance colonic Wnt/β-catenin activation • 15-LOX-1 peroxidation of linoleic acid in PI3P promotes PI3P_13-HODE formation • Low affinity of PI3P_13-HODE for SNX17 inhibits LRP5 recycling Whether Western diet enrichment with linoleic acid promotes colorectal carcinogenesis is poorly understood. Liu et al. identify a mechanism by which 15-lipoxygenase-1 peroxidation of linoleic acid in phosphatidylinositol-3-phosphate (PI3P_LA), to induce PI3P_13-HODE formation, attenuates PI3P binding to the SNX17-LRP5 complex. This inhibits LRP5 recycling, Wnt/β-catenin activation, and colorectal carcinogenesis. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 26391856
- Volume :
- 32
- Issue :
- 7
- Database :
- Complementary Index
- Journal :
- Cell Reports
- Publication Type :
- Academic Journal
- Accession number :
- 145440418
- Full Text :
- https://doi.org/10.1016/j.celrep.2020.108049