TCDD inductions of omega-6 and omega-3 PUFA metabolism act inversely on tumor progression

University Of California Los Angeles, Los Angeles CA

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Abstract

? DESCRIPTION (provided by applicant): The environmental pollutant 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) is the prototype of a large number of non-genotoxic carcinogens, dietary phytochemicals and endogenous metabolites that act via binding the aryl hydrocarbon receptor (AHR). The TCDD-liganded AHR massively upregulates CYP1A1, CYP1A2 and CYP1B1 in many mammalian organs. We previously demonstrated that TCDD treatment markedly increases the levels of epoxides of both w-6 and w-3 polyunsaturated fatty acids (PUFA) in the liver and lungs of mice fed laboratory chow, most likely via the activities of the CYP1 family members. w-6 epoxides are known to stimulate tumor growth, angiogenesis, and metastasis in mice, while w-3 epoxides have the opposite effect. In this application, we propose the overarching hypothesis that TCDD will impact angiogenesis, growth and metastasis of tumors in either a positive or negative way, depending on the relative levels of w-6 epoxides and w-3 epoxides generated in the host and/or tumor cells. To address this overarching hypothesis, four specific aims are proposed. Specific Aim 1 will address the hypothesis that TCDD stimulation of w-6 and w-3 PUFA metabolism both in tissues of the host and in the tumor cells will enhance and inhibit, respectively, the above parameters of tumor progression. Mice will be fed either a high w-6/low w-3 or a low w-6/high w-3 PUFA diet, will be treated with or without TCDD, and then injected subcutaneously with cancer cells that are inducible by TCDD for the CYP1 enzymes. The above parameters of tumor progression will then be quantified. Studies will also address whether the differential effects of w-6 and w-3 PUFA on the induction of metastases by TCDD are independent of any effects of TCDD on primary tumors. An inhibitor of epoxide hydrolase will be utilized to ascertain whether the effects of TCDD are mediated by w-6 and w-3 epoxides. Specific Aim 2 will address the hypothesis that TCDD stimulation of w-6 and w-3 PUFA metabolism in tissues of the host in the absence of TCDD stimulation of PUFA metabolism in the tumor cells will stimulate and inhibit, respectively, the parameters of tumor progression. To ascertain whether the effects of TCDD are mediated by CYP1 enzymes, a Cyp1a1-/- :Cyp1b1-/- double knockout mouse will be utilized. Specific Aim 3 will address the hypothesis that TCDD stimulation of w-6 and w-3 PUFA metabolism within the tumor cells, in the absence of stimulation in the host, will enhance, and inhibit, respectively, tumor growth, angiogenesis and metastasis. Specific Aim 4 will utilize a model in which TCDD promotes the development of primary tumors in mice treated with the tumor initiator, diethylnitrosamine, to investigate whether tumor promotion by TCDD is enhanced by including w-6 PUFA in the diet and inhibited by w-3 PUFA, and to investigate whether promotion is dependent upon PUFA epoxides and CYP1 enzymes. These studies may establish a novel mechanism whereby TCDD stimulates tumor progression; suggest a novel mechanism of cancer protection by w-3 PUFA, and suggest novel mechanisms of action of beneficial dietary AHR agonists and endogenous AHR ligands.