Down-regulation of the phosphoenolpyruvate carboxykinase gene in human colon tumors and induction by omega-3 fatty acids.
The polyunsaturated fatty acid (PUFA) docosahexaenoic acid (DHA) reduces proliferation of several cell types, including colon tumor cells, and regulates gene expression in a cell- and gene-selective manner. In hepatocytes, the fatty acid synthase (FAS) gene is down-regulated by DHA whereas the carnitine palmitoyltransferase-1 (CPT-1) gene is up-regulated. In adipocytes but not in hepatocytes, the expression of the cytosolic phosphoenolpyruvate carboxykinase (PEPCK-C) gene is stimulated by unsaturated FA, including DHA. We monitored the expression of the FAS, CPT-1 and PEPCK-C genes in rat and human colon and in colonic tumors from humans. The ratio of PEPCK-C to FAS transcripts was in favor of PEPCK-C in human and rat colon, whereas the opposite occurred in Caco2 tumoral cells. FAS gene expression declined from proliferative to differentiated Caco2 cells, while in contrast the expression of PEPCK-C and CPT-1 genes increased. DHA strongly induced expression of the PEPCK-C and CPT-1 genes, in correlation with decreased cell growth, while, as expected, it reduced FAS mRNA. We assessed the relative expression of PEPCK-C, CPT-1 and FAS genes in fragments of colonic tumors and adjacent non-tumoral tissue from a series of 10 patients. PEPCK-C and CPT-1 mRNAs are more abundant in non-tumoral tissues than in the tumoral counterpart, whereas the opposite occurred for the FAS gene. Therefore, the PEPCK-C gene can be defined as a new negative marker for colonic tumors and a target for the anti-tumorigenic action of omega-3 PUFAs.
Blouin
Jean-Marc
JM
Institut National de la Santé et de la Recherche Médicale UMR-S 747, Université Paris Descartes, Pharmacologie Toxicologie et Signalisation Cellulaire, 45 rue des Saints-Pères, 75006 Paris, France.
Bortoli
Sylvie
S
Nacfer
Magali
M
Collinet
Martine
M
Penot
Graziella
G
Laurent-Puig
Pierre
P
Forest
Claude
C
D000273:Adipose Tissue / Q000201:enzymology / Q000378:metabolism; D000368:Aged; D000818:Animals; D018938:Caco-2 Cells; D002334:Carnitine O-Palmitoyltransferase / Q000235:genetics; D002454:Cell Differentiation / Q000235:genetics; D049109:Cell Proliferation / Q000187:drug effects; D003106:Colon / Q000201:enzymology / Q000378:metabolism; D003110:Colonic Neoplasms / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D004281:Docosahexaenoic Acids / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects; D064429:Fatty Acid Synthases / Q000235:genetics; D015525:Fatty Acids, Omega-3 / Q000494:pharmacology*; D005260:Female; D020869:Gene Expression Profiling; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D008875:Middle Aged; D010730:Phosphoenolpyruvate Carboxylase / Q000235:genetics*; D051381:Rats; D017207:Rats, Sprague-Dawley; D020133:Reverse Transcriptase Polymerase Chain Reaction
D015525:Fatty Acids, Omega-3; D004281:Docosahexaenoic Acids; D002334:Carnitine O-Palmitoyltransferase; D064429:Fatty Acid Synthases; D010730:Phosphoenolpyruvate Carboxylase