Details

Autor(en) / Beteiligte

• 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

Titel

Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P

Ist Teil von

• Cell reports (Cambridge), 2020-08, Vol.32 (7), p.108049-108049, Article 108049

Ort / Verlag

United States: Elsevier Inc

Erscheinungsjahr

2020

Link zum Volltext

Quelle

MEDLINE

Beschreibungen/Notizen

• 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 (ApcΔ580) 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. [Display omitted] •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.