Effect of gamma-linolenic acid on the transcriptional activity of the Her-2/neu (erbB-2) oncogene.
The omega-6 polyunsaturated fatty acid gamma-linolenic acid (GLA; 18:3n-6), which is found in several plant oils and is used as an herbal medicine, has antitumor activity in vitro. We examined the effect of GLA on the expression of the Her-2/neu (erbB-2) oncogene, which is involved in development of numerous types of human cancer. Flow cytometric and immunoblotting analyses demonstrated that GLA treatment substantially reduced Her-2/neu protein levels in the Her-2/neu-overexpressing cell lines BT-474, SK-Br3, and MDA-MB-453 (breast cancer), SK-OV3 (ovarian cancer), and NCI-N87 (gastrointestinal tumor derived). GLA exposure led to a dramatic decrease in Her-2/neu promoter activity and a concomitant increase in the levels of polyomavirus enhancer activator 3 (PEA3), a transcriptional repressor of Her-2/neu, in these cell lines. In transient transfection experiments, a Her-2/neu promoter bearing a PEA3 site-mutated sequence was not subject to negative regulation by GLA in Her-2/neu-overexpressing cell lines. Concurrent treatments of Her-2/neu-overexpressing cancer cells with GLA and the anti-Her-2/neu antibody trastuzumab led to synergistic increases in apoptosis and reduced growth and colony formation.
Menendez
Javier A
JA
Department of Medicine, Evanston Northwestern Healthcare Research Institute, Evanston, IL 60201, USA. jmenendez@enh.org
Vellon
Luciano
L
Colomer
Ramon
R
Lupu
Ruth
R
D000704:Analysis of Variance; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis / Q000187:drug effects; D001943:Breast Neoplasms / Q000188:drug therapy / Q000235:genetics; D045744:Cell Line, Tumor; D004357:Drug Synergism; D005260:Female; D005434:Flow Cytometry; D005770:Gastrointestinal Neoplasms / Q000188:drug therapy / Q000235:genetics; D018734:Genes, erbB-2 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D015151:Immunoblotting; D009369:Neoplasms / Q000188:drug therapy* / Q000235:genetics*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000187:drug effects* / Q000378:metabolism; D014158:Transcription, Genetic / Q000187:drug effects*; D000068878:Trastuzumab; D017965:gamma-Linolenic Acid / Q000494:pharmacology*
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014157:Transcription Factors; C065788:transcription factor PEA3; D017965:gamma-Linolenic Acid; D000068878:Trastuzumab