Journal Article

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

Seong-Ho Lee, Kiyoshi Yamaguchi, Jong-Sik Kim, Thomas E. Eling, Stephen Safe, Yeonhwa Park and Seung Joon Baek

in Carcinogenesis

Volume 27, issue 5, pages 972-981
Published in print May 2006 | ISSN: 0143-3334
Published online November 2005 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/bgi268
Conjugated linoleic acid stimulates an anti-tumorigenic protein NAG-1 in an isomer specific manner

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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-β 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-3β pathway in human CRC cells.

Keywords: AHPN, 6-[3-(1-adamantyl)-4-hydroxyphenyl]-2-naphthalene carboxylic acid; ATF3, activating transcription factor3; c9,t11-CLA, cis-9, trans-11 isomer of CLA; CHX, cycloheximide; CLA, conjugated linoleic acid; CRC, colorectal cancer; CREB, cAMP response element binding protein; GSK-3, glycogen synthase kinase-3; IGF-1, insulin-like growth factor-1; LA, linoleic acid; LBD, ligand binding domain; NAG-1, NSAID-activated gene-1; NSAIDs, non-steroidal anti-inflammatory drugs; PI3K, phosphatidylinositol 3-kinase; PPAR, peroxisome proliferator-activated receptor; t10,c12-CLA, trans-10, cis-12 isomer of CLA

Journal Article.  7689 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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