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Carcinogenesis Advance Access published online on November 14, 2005
Carcinogenesis, doi:10.1093/carcin/bgi268
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© The Author 2005. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oxfordjournals.org
Received March 29, 2005
Revised October 14, 2005
Accepted November 9, 2005

MOLECULAR EPIDEMIOLOGY AND CANCER PREVENTION

Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner

Seong-Ho Lee 1, Kiyoshi Yamaguchi 1, Jong-Sik Kim 2, Thomas E. Eling 3, Stephen Safe 4, Yeonhwa Park 5, and Seung Joon Baek 1 *

1 Department of Pathobiology, College of Veterinary Medicine, University of Tennessee, Knoxville, TN 37996
2 Department of Biological Science, Andong National University, Andong, Korea
3 Laboratory of Molecular Carcinogenesis, National Institute of Environmental Health Sciences, National Institutes of Health, Research Triangle Park, NC 27709
4 Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station, TX 77843
5 Department of Food Science, University of Massachusetts, Amherst, MA01003

* To whom correspondence should be addressed.
Seung Joon Baek, E-mail: sbaek2{at}utk.edu


  Abstract

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 (nonsteroidal anti-inflammatory drug-activated gene-1) is induced by several dietary compounds and belongs to a TGF-{beta} 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 cells. The tran-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 colorectal cancer cells. Inhibition of NAG-1 expression by 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-3{beta} pathway in human colorectal cancer cells.

Keywords: CLA; NAG-1; ATF3; GSK-3; apoptosis.
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