Carcinogenesis Advance Access originally published online on November 14, 2005
Carcinogenesis 2006 27(5):972-981; doi:10.1093/carcin/bgi268
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Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner
Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996, USA, 1 Department of Biological Science, Andong National University, Andong, Korea, 2 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709, USA, 3 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843, USA and 4 Department of Food Science, University of Massachusetts, Amherst, MA 01003, USA
* To whom correspondence should be addressed at: Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, 2407 River Drive, Knoxville, TN 37996-4542, USA. Tel: +1 865 974 8216; Fax: +1 865 974 5616; Email: sbaek2{at}utk.edu
Conjugated linoleic acids (CLAs), naturally occurring fatty acids in ruminant food products, have anti-tumorigenic and pro-apoptotic properties in animal as well as in vitro models of cancer. However, the cellular mechanism has not been fully understood. NAG-1 (non-steroidal anti-inflammatory drug-activated gene-1) is induced by several dietary compounds and belongs to a TGF-ß superfamily gene associated with pro-apoptotic and anti-tumorigenic activities. The present study was performed to elucidate the molecular mechanism by which CLA stimulates anti-tumorigenic activity in human colorectal cancer (CRC) cells. The trans-10, cis-12-CLA (t10,c12-CLA) repressed cell proliferation and induced apoptosis, whereas linoleic acid or c9,t11-CLA showed no effect on cell proliferation and apoptosis. We also found that t10,c12-CLA induced the expression of a pro-apoptotic gene, NAG-1, in human CRC cells. Inhibition of NAG-1 expression by small interference RNA (siRNA) results in repression of t10,c12-CLA-induced apoptosis. Microarray analysis using t10,c12-CLA-treated HCT-116 cells revealed that activating transcription factor 3 (ATF3) was induced and its expression was confirmed by western analysis. The t10,c12-CLA treatment followed by the overexpression of ATF3 increased NAG-1 promoter activity in HCT-116 cells. We further provide the evidence that t10,c12-CLA inhibited the phosphorylation of AKT and the blockage of GSK-3 by siRNA abolished t10,c12-CLA-induced ATF3 and NAG-1 expression. The current study demonstrates that t10,c12-CLA stimulates ATF3/NAG-1 expression and subsequently induces apoptosis in an isomer specific manner. These effects may be through inhibition of AKT/GSK-3ß pathway in human CRC cells.
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