Department of Pathology & Laboratory Medicine, University of California, Los Angeles, CA, 90095, USA.
Research Unit of Oncology Diseases. Hospital Infantil de Mexico, Federico Gomez, Mexico City, Mexico.
Sci Rep. 2020 May 12;10(1):7843. doi: 10.1038/s41598-020-64146-6.
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.
西方饮食中含有高比例的ω-6（ω6）与 ω-3（ω3）多不饱和脂肪酸（PUFA）。典型的芳基烃受体（AHR）配体，2,3,7,8-四氯二苯并-p-二恶英（TCDD），可诱导 CYP1 家族酶，将 PUFA 代谢为环氧化物。用富含 ω3 或 ω6 的饮食喂养的小鼠接受 TCDD 处理，并皮下注射 AHR 有效 Hepa1-GFP 肝癌细胞或 AHR 缺陷 LLC 肺癌细胞。TCDD 降低了 ω3 喂养小鼠中产生的肿瘤的生长速度，并抑制了它们向肝脏和/或肺部的转移，但在 ω6 PUFA 喂养的小鼠中则产生了相反的效果。这些反应可能归因于肿瘤细胞和/或宿主中产生的相应 PUFA 环氧化物，因为许多反应在雄性中需要共给予可溶性环氧化物水解酶（EPHX2）抑制剂，并且/或与肿瘤和转移部位中环氧化物水平的增加有关。在没有 EPHX2 抑制的情况下，雌性中也出现了等效的作用，可能是因为这种性别表达的 EPHX2 水平降低。TCDD 引起的反应与肿瘤血管生成、肿瘤细胞增殖和/或凋亡有关。因此，环境 AHR 激动剂，以及潜在的内源性、营养性和微生物组衍生的激动剂，可能会根据饮食中 PUFA 的组成，特别是在女性中，减少或增强癌症的进展。
