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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.

Authors :
Liu, Fuyao
Zuo, Xiangsheng
Liu, Yi
Deguchi, Yasunori
Moussalli, Micheline J.
Chen, Weidong
Yang, Peiying
Wei, Bo
Tan, Lin
Lorenzi, Philip L.
Gao, Shen
Jaoude, Jonathan C.
Mehdizadeh, Amir
Valentin, Lovie Ann
Wei, Daoyan
Shureiqi, Imad
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