Aryl Hydrocarbon Receptor-Dependent inductions of omega-3 and omega-6 polyunsaturated fatty acid metabolism act inversely on tumor progression

Abstract

The Western diet contains a high ratio of omega-6 (ω6) to omega-3 (ω3) polyunsaturated fatty acids (PUFA). The prototypical aryl hydrocarbon receptor (AHR) ligand, 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD), induces CYP1 family enzymes, which can metabolize PUFA to epoxides. Mice fed ω3-rich or ω6-rich diets were treated with TCDD and injected subcutaneously with AHR-competent Hepa1-GFP hepatoma cells or AHR-deficient LLC lung cancer cells. TCDD reduced the growth rates of the resulting tumors in ω3-fed mice and inhibited their metastasis to the liver and/or lung, but had the opposite effects in mice fed ω6 PUFA. These responses were likely attributable to the corresponding PUFA epoxides generated in tumor cells and/or host, since many depended upon co-administration of a soluble epoxide hydrolase (EPHX2) inhibitor in males, and/or were associated with increases in epoxide levels in tumors and sites of metastasis. Equivalent effects occurred in females in the absence of EPHX2 inhibition, probably because this sex expressed reduced levels of EPHX2. The responses elicited by TCDD were associated with effects on tumor vascularity, tumor cell proliferation and/or apoptosis. Thus environmental AHR agonists, and potentially also endogenous, nutritional, and microbiome-derived agonists, may reduce or enhance cancer progression depending on the composition of dietary PUFA, particularly in females. The aryl hydrocarbon receptor (AHR) binds a number of environmental pollutants, including 2,3,7,8-Tetra chlorodibenzo-ρ-dioxin (TCDD), polychlorinated biphenyls (PCBs), and certain polycyclic aromatic hydrocarbons (PAHs), some endogenous metabolites, including the tryptophan catabolite kynurenine, certain products generated by commensal microbes and dietary components, including compounds found in cruciferous vegetables 1-4. After binding TCDD and other ligands, the AHR turns on the transcription of a large number of genes. CYP1A1, CYP1A2 and CYP1B1 are induced in many tissues in all mammals, and are also generally the most massively induced genes 5,6. Interestingly, TCDD and other AHR agonists can both enhance or retard tumor growth in experimental mouse models, depending on context 7,8. High intake of omega-6 (ω6) polyunsaturated fatty acids (PUFA) such as arachidonic acid (ARA) and linoleic (LA) acid, characteristic of the western diet, is linked to a number of adverse health effects, including cancer. In contrast, the omega 3 (ω3) PUFAs, α-linolenic acid (ALA), eicosapentaenoic acid (EPA), and docosahexaenoic acid (DHA) are generally correlated with beneficial health effects 9. PUFA are metabolized through three pathways: the "cyclooxygenase", "lipoxygenase" and the lesser studied "cytochrome P450 epoxidation/hydroxylation" pathways (see Fig. 1a for the metabolism of ARA). PUFA epoxides are further metabolized to diols, which are generally considered less biologically active, by soluble epoxide hydrolase (EPHX2) 10. Increasing the levels of

How the AHR Became Important in Cancer: The Role of Chronically Active AHR in Cancer Aggression

“…These findings provided a ready explanation for the association between the AHR and cancer. That is, nominally “resting” AHR was seen to be activated by environmental chemicals to induce Phase 1 P450 hydroxylases that generate mutagenic intermediates from the pro-carcinogen parent compounds or from some endogenous substrates (e.g., estradiol or polyunsaturated fats [ 31 , 32 , 33 ]). These intermediates mutate DNA and initiate cancer.…”

How Changes in the Nutritional Landscape Shape Gut Immunometabolism

“…Finally, how diet composition might interfere with the immune impact of AhR ligands is unknown. A recent study has shown that the AhR ligand TCDD reduced tumor growth in mice fed on an Omega-3 fatty acid-enriched diet while an Omega-6 fatty acid-enriched diet aggravated tumor growth [ 158 ]. While this study focused on the direct impact of AhR on tumor cells, the differential effect of AhR ligands on the Treg/Th17 balance depending on the dietary context cannot be excluded.…”

Food, Nutrition, Physical Activity and Microbiota: Which Impact on Lung Cancer?

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