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.
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DOI：
10.1016/j.celrep.2020.108049
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发表时间：
2020-08-18
期刊：
影响因子：
8.8
通讯作者：
Shureiqi I
中科院分区：
文献类型：
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作者：
Liu F;Zuo X;Liu Y;Deguchi Y;Moussalli MJ;Chen W;Yang P;Wei B;Tan L;Lorenzi PL;Gao S;Jaoude JC;Mehdizadeh A;Valentin LA;Wei D;Shureiqi I
APC突变激活Wnt/β-catenin驱动结直肠癌（CRC）的启动。其他因素增强β-catenin的激活以促进结直肠癌。西方饮食富含亚油酸（LA）；富含la的饮食促进啮齿动物化学诱导的结直肠癌。15-脂氧合酶-1 （15-LOX-1）是主要的la代谢酶，在结直肠癌期间转录沉默。LA和15-LOX-1是否影响Wnt/β-catenin信号传导尚不清楚。我们报道，高饮食LA通过上调Wnt受体LRP5蛋白表达和β-catenin激活，促进了偶氮氧甲烷处理或肠道靶向Apc突变（ApcΔ580）小鼠的结直肠癌。15-LOX-1转基因在小鼠肠上皮细胞中的表达可抑制LRP5蛋白表达、β-catenin活化和结直肠癌。磷脂酰肌醇-3-磷酸（PI3P_LA）中LA的15-LOX-1过氧化导致PI3P_13-HODE形成，从而降低PI3P与SNX17和LRP5的结合，抑制LRP5从核内体再循环到质膜，从而增加LRP5溶酶体降解。这种LRP5/Wnt/β-catenin信号的调控机制可以作为抑制结直肠癌的治疗靶点。西方饮食中富集亚油酸是否促进结直肠癌的发生尚不清楚。Liu等人确定了磷脂酰肌醇-3-磷酸（PI3P_LA）中亚油酸15-脂氧合酶-1过氧化诱导PI3P_13-HODE形成的机制，该机制减弱了PI3P与SNX17-LRP5复合物的结合。这抑制了LRP5再循环、Wnt/β-连环蛋白激活和结直肠癌的发生。
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. 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.