Endogenous conversion of-6 to-3 polyunsaturated fatty acids in fat-1 mice attenuated intestinal polyposis by either inhibiting COX-2/-catenin signaling or activating 15-PGDH/IL-18

Abstract

Omega-3 polyunsaturated fatty acids (-3PUFAs) have inhibitory effects in various preclinical cancer models, but their effects in intestinal polyposis have never been examined. As attempts have been made to use nutritional intervention to counteract colon cancer development, in this study we evaluated the effects of -3 PUFAs on intestinal polyposis in the Apc(Min/+) mouse model. The experimental groups included wild-type C56BL/6 mice, Apc(Min/+) mice, fat-1 transgenic mice expressing an n-3 desaturase to enable -3 PUFA synthesis, and Apc(Min/+) x fat-1 double-transgenic mice; all mice were 20 weeks of age. Small intestines were collected for gross and pathologic evaluation, including assessment of polyp number and size, followed by immunohistochemical staining and Western blotting. After administration of various concentrations of -3 PUFAs, PUFA levels were measured in small intestine tissue by GC/MS/MS analysis to compare with PUFA synthesis of between C57BL6 and fat-1mice. As a result, -3 PUFAs significantly attenuated Apc mutation-induced intestinal polyposis accompanied with significant inhibition of Wnt/-catenin signaling, COX-2 and PGE(2,) but induced significant levels of 15-PGDH. In addition, significant induction of the inflammasome-related substrates as IL-1 and IL-18 and activation of caspase-1 was observed in Apc(Min/+) x fat-1 mice. Administration of at least 3 g/60 kg -3 PUFAs was equivalent to -3 PUFAs produced in fat-1 mice and resulted in significant increase in the expression of IL-1, caspase-3 and IL-18, as seen in Apc(Min/+) x fat-1 mice. We conclude that -3PUFAs can prevent intestinal polyp formation by inhibition of Wnt/-catenin signaling, but increased levels of 15-PGDH and IL-18. What's new? The cancer-preventive potential for omega-3 polyunsaturated fatty acids (-3 PUFAs) is of great clinical interest, especially in the case of colorectal cancer, which is strongly influenced by diet. However, the mechanistic basis by which -3 PUFAs suppress polyp formation remains largely unknown. In this study, the suppressive effects of -3 PUFAs on intestinal polyposis in vivo were linked to the inhibition of COX-2 and Wnt/-catenin signaling and to the induction of 15-PGDH and IL-18. The findings suggest that -3 PUFA intake is clinically relevant, particularly following polypectomy and in the surveillance of familial adenomatous polyposis.