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Publication Detail

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

Authors: Huerta-Yepez, Sara; Tirado-Rodriguez, Ana; Montecillo-Aguado, Mayra R; Yang, Jun; Hammock, Bruce D; Hankinson, Oliver

Published In Sci Rep, (2020 05 12)

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.

PubMed ID: 32398692 Exiting the NIEHS site

MeSH Terms: Animals; Apoptosis/drug effects; Cell Count; Cell Line, Tumor; Cell Proliferation/drug effects; Cell Transformation, Neoplastic; Diet; Disease Progression*; Fatty Acids, Omega-3/metabolism*; Fatty Acids, Omega-3/pharmacology; Fatty Acids, Omega-6/metabolism*; Fatty Acids, Omega-6/pharmacology; Female; Humans; Lung Neoplasms/pathology*; Male; Mice; Receptors, Aryl Hydrocarbon/metabolism*; Vascular Endothelial Growth Factor A/metabolism

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