Conjugated linoleic acid attenuates cyclooxygenase-2 transcriptional activity via an anti-AP-1 mechanism in MCF-7 breast cancer cells.

Abstract

Overexpression of cyclooxygenase-2 (COX-2) is regarded as a causative factor in the onset of tumorigenesis of the breast. In this study, we investigated the effects of conjugated linoleic acid (CLA) on COX-2 transcription in MCF-7 breast cancer cells. Results of transient transfection studies revealed that treatment with a CLA mix or selected isomers (c9, t11-CLA; t10, c12-CLA) at concentrations ranging from 20 to 80 micromol/L, attenuated COX-2 transcription induced by the proinflammatory agent 12-O-tetradecanoylphorbol-13-acetate (TPA). In addition, the CLA mix inhibited TPA-induced activity of the collagenase-1 promoter. Using electrophoretic mobility shift assays, we found that the CLA mix reduced TPA-induced recruitment of nuclear proteins to a cAMP response element (CRE) in the COX-2 promoter and a consensus TPA-responsive element (TRE) in the collagenase-1 promoter. Both CRE and TRE are binding sites for activator protein-1 (AP-1). Binding studies revealed that the t10, c12-CLA isomer was more effective than the CLA mix or c9, t11-CLA in reducing binding of cJun to either the COX-2 CRE or collagenase-1 TRE, whereas linoleic acid increased binding to both elements. Overexpression of the AP-1 member, c-Jun, reversed the inhibitory effects of the CLA mix on COX-2 transcription, and restored binding of nuclear proteins to the CRE and TRE. Collectively, these results suggest that CLA represses AP-1-mediated activation of COX-2 transcription.

• Authors: Stephanie C Degner, Michael Q Kemp, G Tim Bowden, Donato F Romagnolo
• Journal: The Journal of nutrition (J Nutr) Vol. 136 Issue 2 Pg. 421-7 (Feb 2006) ISSN: 0022-3166 [Print] United States
• PMID: 16424122 (Publication Type: Journal Article)

Chemical References

• Linoleic Acids, Conjugated
• Nuclear Proteins
• Proto-Oncogene Proteins c-jun
• Transcription Factor AP-1
• Cyclic AMP
• Cyclooxygenase 2
• Tetradecanoylphorbol Acetate

Topics

• Breast Neoplasms (genetics, metabolism)
• Cell Line, Tumor
• Cyclic AMP (metabolism)
• Cyclooxygenase 2 (genetics, metabolism)
• Humans
• Linoleic Acids, Conjugated (pharmacology)
• Nuclear Proteins (metabolism)
• Promoter Regions, Genetic (genetics)
• Protein Binding
• Proto-Oncogene Proteins c-jun (metabolism)
• Response Elements (genetics)
• Signal Transduction
• Tetradecanoylphorbol Acetate (pharmacology)
• Transcription Factor AP-1 (antagonists & inhibitors, metabolism)
• Transcription, Genetic (drug effects, genetics)