Abstract
Background & aims:
Eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), the major omega-3 polyunsaturated fatty acids (ω-3 PUFAs), derived from fish oil are widely used as dietary supplements and are United States Food and Drug Administration (FDA)-approved for treating hypertriglyceridemia. However, studies evaluating their effects on colorectal tumorigenesis (CRT) have produced conflicting results, and the underlying reasons for this variability remain unclear. 15-Lipoxygenase-1 (ALOX15), a key enzyme involved in the generation of resolvins from EPA and DHA, is frequently lost in the human colon during CRT. We therefore investigated whether ALOX15 expression in the colon influences the effects of EPA and DHA on resolvin production and CRT.
Methods:
The effects of intestinal transgenic ALOX15 expression on resolvin generation and colorectal tumor formation in response to various formulations of EPA and DHA dietary supplementations were evaluated using multiple mouse models that closely recapitulate human CRT. Transgenic human ALOX15 was expressed in colonic epithelial cells under the control of various promoters in the mice. EPA, DHA and their metabolite resolvin levels were assessed in colonic epithelial cells and sera by liquid chromatography and tandem mass spectrometry, whereas production of chemokines and cytokines (eg, C-C motif chemokine ligand 3-5 [CCL3-5], interleukin-1 beta [IL-1β], interleukin-6 [IL-6]) was measured. Abundance of tumor-associated macrophages and CD8+ T cells was evaluated by immunohistochemistry and immunofluorescence staining.
Results:
Dietary EPA and DHA supplementation in control mice lacking transgenic human ALOX15 expression resulted in minimal changes in resolvin production and had variable effects on CRT. In contrast, EPA and DHA uniformly inhibited colorectal tumor formation in mice engineered to express human ALOX15 in their intestinal epithelial cells. These antitumorigenic effects were associated with increased resolvin production, reduced colonic expression of CCL2, IL-1β, and IL-6, decreased tumor-associated macrophages, and enhanced infiltration of CD8α+ T cells in the tumor microenvironment. In vitro, resolvin E (RvE)1 and resolvine D (RvD)5-the predominant resolvins generated by ALOX15-suppressed CCL2, IL-1β, and IL-6 production and promoted phagocytic activity in murine macrophages.
Conclusions:
Colonic ALOX15 expression is essential for enabling EPA and DHA to generate resolvins and consistently suppress CRT. The status of colonic ALOX15 expression should be taken into account when developing prevention strategies that utilize EPA and DHA to decrease the risk of colon cancer.