Aryl Hydrocarbon Receptor-Mediated Induction of CYP1A1 and CYP1B1 Enzymes in Brain: A Preliminary Exploration of the Role of Oxylipins in Lung Cancer Metastasis to Brain

Lung cancer is one of the most frequent diagnosis cancers in the U.S. Importantly, primary lung cancer frequently metastasizes to brain, but the survival and treatment of lung cancer brain metastasis are both poor. Aryl Hydrocarbon Receptor (AHR) mediated induction of Cytochrome P450 enzymes has been linked to cancer progression via binding to AHR agonists like 2, 3, 7, 8-tetrachlorodibenzo-p-dioxin (TCDD). The exposure of TCDD significantly increases CYP 1A1 and CYP 1B1 in the lung and liver. The western diet typically contains a high ratio of omega-6 (-6) to omega-3 (-3) polyunsaturated fatty acids (PUFA). Recently, our group has demonstrated that the action of -6 and -3 PUFA metabolism on tumor progression is an AHR dependent process. TCDD promotes tumor growth and metastasis under -6 enriched diets but inhibits tumor growth and metastasis under -3 enriched diets. This finding indicates that TCDD impact on lung cancer progression can be modified by dietary PUFA. Based on this new research ground, it is also interesting to evaluate TCDD’s action on primary lung cancer metastasis to the brain depending on different ratio of -6 to -3 PUFA in diet. We hypothesized that the lung tumor increases the metastasis to the brain through, an AHR agonist like TCDD, which induce the expression of some cytochrome P450 in the brain of the mice that were fed with rich-⍵6 diet. To evaluate our hypothesis, we performed immunohistochemistry, digital pathology, RT-PCR, and liquid chromatography with tandem mass spectrometry. Our data demonstrated that the brain metastasis was found in mice fed with rich- ω-6 diet in mice treated with TCDD as compared with untreated mice. Further, TCDD significantly induced CYP 1A1 and CYP 1B1 in mice brain tissue under ω-6 enriched diet. In addition, the levels of oxylipins in plasma demonstrated that epoxides 5,6 EET are increases after TCCD treatment, as well as various diols like 5,6-DiHETrE, 11,12-DiHETrE, and 14,15-DiHETrE.These results provide us a future research direction on combining effects of diets and environment carcinogens to analyze the mechanism to be involved in the metastasis to the brain from the lung tumor cells