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Biochemical, Molecular, and Genetic Mechanisms

PPAR1 as a Molecular Target of Eicosapentaenoic Acid in Human Colon Cancer (HT-29) Cells^1,2

³ Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843 and ⁴ Department of Molecular and Biomedical Pharmacology, University of Kentucky, Lexington, KY 40536

^* To whom correspondence should be addressed. E-mail: callred{at}tamu.edu.

Diets high in (n-3) PUFA decrease colon cancer development and suppress colon tumor growth, but the molecular mechanism through which these compounds act is largely unknown. We sought to determine whether PPAR1 serves as a molecular link between the physiological actions of eicosapentaenoic acid (EPA) in human colon cancer cells (HT-29). At nutritionally relevant concentrations, EPA stimulated a PPAR response element (PPRE) reporter assay in a dose-responsive manner in HT-29 cells. Cotreatment with GW9662 (GW), a PPAR antagonist, significantly inhibited this effect, whereas overexpressing the receptor enhanced it. EPA also stimulated the PPRE reporter in a PPAR negative cancer cell line (22Rv1) when the cells were cotransfected with a PPAR1 expression plasmid and this effect was again inhibited by GW. Furthermore, in vitro incubation of EPA with PPAR1 enhanced binding of the protein to DNA containing a PPRE. Next, we sought to determine whether EPA or a prostaglandin formed from EPA is the functional ligand of PPAR. Cotreatment in HT-29 and 22Rv1 cells with EPA and acetyl salicylic acid, an inhibitor of cyclooxygenase activity, activated the PPRE reporter at levels similar to EPA alone, suggesting that EPA itself is a ligand of PPAR. Finally, EPA suppressed HT-29 cell growth and this effect was significantly reversed by the addition of GW, suggesting that in part the physiological actions of EPA are the result of PPAR activation. These studies identify PPAR as a molecular mediator of (n-3) PUFA actions in colon cancer cells.

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