Suppression of membranous LRP5 recycling, WNT/β-catenin signaling, and colorectal tumorigenesis by 15-LOX-1 peroxidation of PI3P_linoleic acid

Abstract

Aberrant Wnt/β-catenin activation is a major driver of colorectal cancer (CRC), which is typically initiated by APC mutations. Additional modifiable factors beyond APC mutations have been recognized to be important for further potentiation of aberrant β-catenin activation to promote colorectal tumorigenesis. These factors have yet to be clearly identified. Western-type diets are increasingly enriched in linoleic acid (LA). LA-enriched diet however promotes chemically-induced colorectal tumorigenesis in rodent models. Furthermore, the main metabolizing enzyme of LA, 15-lipoxygenase-1 (15-LOX-1), is transcriptionally silenced in CRC. Whether LA and 15-LOX-1 affect Wnt/β-catenin signaling to modulate colorectal tumorigenesis is poorly understood. Herein, we report that high dietary LA promoted colorectal tumorigenesis in mice with intestinally targeted APC mutation (Apc Δ580 ) by upregulating a Wnt receptor, LRP5 expression, and β-catenin activation. 15-LOX-1 transgenic expression in intestinal epithelial cells suppressed LRP5 expression, β-catenin activation and subsequently CRC in these mice. In particular, 15-LOX-1 peroxidation of LA in phosphatidylinositol-3-phosphates (PI3P_LA) into PI3P_13-HODE decreased PI3P binding to SNX17and LRP5, which inhibited LRP5 recycling from endosomes to the plasma membrane, thereby leading to an increase of LRP5 lysosomal degradation. Our findings demonstrate for the first time that 15-LOX-1 metabolism of LA in PI3P to regulate LRP5 membrane abundance is a modifiable factor of Wnt/β-catenin aberrant signaling that could be potentially therapeutically targeted to suppress colorectal tumorigenesis and progression.

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“…Tumorassociated linoleate and its 15-LOX-1-dependent intermediates were lower in Pirc controls fed basal AIN diet, and they were normalized in adenomatous polyps after SPI treatment (Fig. 7a), consistent with the proposed anticancer mechanisms of these metabolites [25][26][27]. Several other intermediates associated with fatty acid metabolism also were detected in metabolomic analyses, such as 6-keto-prostaglandin E 1 (6-keto-PGE 1 ) and PGE 2 ethanolamine; changes after SPI consumption were consistent with an overall shift towards anti-in ammatory, proapoptotic and tumor suppression pathways (Additional le 5).…”

“…Several other intermediates associated with fatty acid metabolism also were detected in metabolomic analyses, such as 6-keto-prostaglandin E 1 (6-keto-PGE 1 ) and PGE 2 ethanolamine; changes after SPI consumption were consistent with an overall shift towards anti-in ammatory, proapoptotic and tumor suppression pathways (Additional le 5). Thus, in SPI-fed rats, a decreased ux through pro-in ammatory leukotrienes and prostaglandins was paralleled by increased levels of 9-LOX, 15-LOX-1, prostacyclin, and cytochrome P450 (CYP) metabolites that are linked to anticancer outcomes [25][26][27].…”

“…7). Linoleate and its downstream metabolites from the 15-lipoxygenase-1 (15-LOX-1) pathway exert proapoptotic antitumor mechanisms in CRC [25][26][27]; notably, lower levels of these metabolites in Pirc colon tumors tended to be normalized in adenomatous polyps following SPI treatment, comparable to the levels detected in normal-looking Pirc colon ±SPI (Fig. 7a).…”