PPARgamma1 as a molecular target of eicosapentaenoic acid in human colon cancer (HT-29) cells.
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 PPARgamma1 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 PPARgamma antagonist, significantly inhibited this effect, whereas overexpressing the receptor enhanced it. EPA also stimulated the PPRE reporter in a PPARgamma negative cancer cell line (22Rv1) when the cells were cotransfected with a PPARgamma1 expression plasmid and this effect was again inhibited by GW. Furthermore, in vitro incubation of EPA with PPARgamma1 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 PPARgamma. 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 PPARgamma. 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 PPARgamma activation. These studies identify PPARgamma as a molecular mediator of (n-3) PUFA actions in colon cancer cells.
Allred
Clinton D
CD
Department of Nutrition and Food Science, Texas A&M University, College Station, TX 77843, USA. callred@tamu.edu
Talbert
Dominique R
DR
Southard
R Chase
RC
Wang
Xin
X
Kilgore
Michael W
MW
D000813:Anilides / Q000494:pharmacology; D049109:Cell Proliferation; D003110:Colonic Neoplasms / Q000378:metabolism*; D015118:Eicosapentaenoic Acid / Q000494:pharmacology*; D005786:Gene Expression Regulation; D019073:HT29 Cells; D006801:Humans; D008297:Male; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism; D011485:Protein Binding; D020218:Response Elements / Q000502:physiology; D000077154:Rosiglitazone; D045162:Thiazolidinediones / Q000494:pharmacology
C457499:2-chloro-5-nitrobenzanilide; D000813:Anilides; D047495:PPAR gamma; D045162:Thiazolidinediones; D000077154:Rosiglitazone; C089946:2,4-thiazolidinedione; D015118:Eicosapentaenoic Acid