التفاصيل البيبلوغرافية
| العنوان: |
Suppression of Membranous LRP5 Recycling, Wnt/β-Catenin Signaling, and Colon Carcinogenesis by 15-LOX-1 Peroxidation of Linoleic Acid in PI3P. |
| المؤلفون: |
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 |
| المصدر: |
Cell Reports; Aug2020, Vol. 32 Issue 7, pN.PAG-N.PAG, 1p |
| مستخلص: |
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. • 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] |
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| قاعدة البيانات: |
Complementary Index |
