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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
- Source :
- Cell Rep
- Publication Year :
- 2019
-
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(Δ580)) 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.
- Subjects :
- 0301 basic medicine
Colorectal cancer
Endosome
Transgene
medicine.disease_cause
Transfection
General Biochemistry, Genetics and Molecular Biology
Article
Linoleic Acid
03 medical and health sciences
chemistry.chemical_compound
Mice
0302 clinical medicine
medicine
Animals
Humans
Receptor
Wnt Signaling Pathway
beta Catenin
Mutation
Azoxymethane
Wnt signaling pathway
LRP5
medicine.disease
030104 developmental biology
Low Density Lipoprotein Receptor-Related Protein-5
chemistry
Colonic Neoplasms
Cancer research
030217 neurology & neurosurgery
Signal Transduction
Subjects
Details
- ISSN :
- 22111247
- Volume :
- 32
- Issue :
- 7
- Database :
- OpenAIRE
- Journal :
- Cell reports
- Accession number :
- edsair.doi.dedup.....20fe33c7905d9d72cfdc5c94d767acc2