Molecular and cellular effects of cis-9, trans-11-conjugated linoleic acid in enterocytes: effects on proliferation, differentiation, and gene expression.
It has been hypothesized that dietary conjugated linoleic acids (CLA) may inhibit colon tumorigenesis. The aim of our study was to investigate the cellular and molecular effects of cis-9 (9Z), trans-11 (11E)-CLA on the proliferation, differentiation, interaction with peroxisome proliferator-activated receptors (PPARs), and expression of genes relevant in the APC-beta-catenin-TCF4 signalling pathway in human HT-29 and Caco-2 colon cells. We found that 9Z,11E-CLA inhibited the proliferation of HT-29 and Caco-2 cells. Trans-vaccenic acid (VA) showed no antiproliferative effects at all. We determined that 9Z,11E-CLA induced cell differentiation as measured by intestinal alkaline phosphatase (IAP) enzyme activity in Caco-2 cells, mRNA expression of IAP, and activation of a 5' flanking region of IAP. The 9Z,11E-CLA activated human PPARdelta as measured in a reporter gene assay. Treatment of HT29 cells in the poliferation phase with 9Z,11E-CLA repressed mRNA-expression of proliferation genes such as c-myc, cyclin D1 and c-jun in a concentration dependent manner. The promoter activities of c-myc and AP1 were also inhibited after incubation with 9Z,11E-CLA. beta-Catenin mRNA and protein expression was also repressed by the treatment with 9Z,11E-CLA. In addition, the mRNA expression of PPARdelta was repressed by treatment of the HT-29 cells with 9Z,11E-CLA. We conclude that 9Z,11E-CLA has an antiproliferative effect at the cellular and molecular levels in human colon cells. The results indicate that the preventive effects of CLA in the development of colon cancer may be due to their downregulation of some target genes of the APC-beta-catenin-TCF-4- and PPARdelta signalling pathway.
Lampen
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Institut für Lebensmitteltoxikologie, Stiftung Tierärztliche Hochschule Hannover, Germany. Alfonso.Lampen@tiho-hannover.de
Leifheit
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Voss
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Nau
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D000199:Actins / Q000032:analysis / Q000235:genetics; D015415:Biomarkers; D018938:Caco-2 Cells; D002448:Cell Adhesion / Q000187:drug effects; D002454:Cell Differentiation / Q000187:drug effects*; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D003598:Cytoskeletal Proteins / Q000032:analysis / Q000235:genetics; D020895:Enterocytes / Q000166:cytology* / Q000187:drug effects* / Q000378:metabolism; D005786:Gene Expression Regulation / Q000187:drug effects*; D016259:Genes, myc / Q000235:genetics; D019073:HT29 Cells; D006801:Humans; D007668:Kidney / Q000166:cytology; D044243:Linoleic Acids, Conjugated / Q000378:metabolism / Q000494:pharmacology*; D047494:PPAR delta / Q000819:agonists / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013237:Stereoisomerism; D015534:Trans-Activators / Q000032:analysis / Q000235:genetics; D051176:beta Catenin
D000199:Actins; D015415:Biomarkers; C495270:CTNNB1 protein, human; D003598:Cytoskeletal Proteins; D044243:Linoleic Acids, Conjugated; D047494:PPAR delta; D012333:RNA, Messenger; D015534:Trans-Activators; D051176:beta Catenin; C503589:cis-9, trans-11-conjugated linoleic acid