The aryl hydrocarbon receptor antagonist, 3'methoxy-4'nitroflavone, attenuates 2,3,7,8-tetrachlorodibenzo-p-dioxin-dependent regulation of growth factor signaling and apoptosis in the MCF-10A cell line

• Published in: Toxicology and applied pharmacology 2003-04, Vol.188 (1), p.42-49
• Main Authors: DAVIS, John W, BURDICK, Andrew D, LAUER, Fredine T, BURCHIEL, Scott W
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Biological and medical sciences; Cell Line; Chemical and industrial products toxicology. Toxic occupational diseases; Epithelial Cells - drug effects; Epithelial Cells - metabolism; ErbB Receptors - metabolism; Flavonoids - pharmacology; Humans; Medical sciences; Mitogen-Activated Protein Kinase 1 - metabolism; Mitogen-Activated Protein Kinase 3; Mitogen-Activated Protein Kinases - metabolism; Phosphorylation; Polychlorinated Dibenzodioxins - toxicity; Protein-Serine-Threonine Kinases; Proto-Oncogene Proteins - metabolism; Proto-Oncogene Proteins c-akt; Receptors, Aryl Hydrocarbon - antagonists & inhibitors; Signal Transduction - drug effects; Toxicology; Transforming Growth Factor alpha - biosynthesis; Various organic compounds
• ISSN: 0041-008X; 1096-0333
• DOI: 10.1016/S0041-008X(03)00012-7

Previous studies have demonstrated that 2,3,7,8 tetracholorodibenzo-p-dioxin (TCDD) mimics epidermal growth factor receptor (EGFR) signaling in the MCF-10A human mammary epithelial cell line and protects cells from EGF withdrawal-induced apoptosis. These effects appear to be due to the ability of TCDD to increase the expression of transforming growth factor-alpha (TGFalpha), a known EGFR ligand. Because TCDD's effects occurred at concentrations as low as 1 nM, a role for the aryl hydrocarbon receptor (AhR) was hypothesized. In the present study, 3'methoxy-4'nitroflavone (MNF), a known AhR antagonist, was used to analyze AhR signaling in this cell line. MNF suppressed TCDD-dependent dioxin response element (DRE)-driven luciferase activity at concentrations as low as 10 nM. In addition, MNF attenuated TCDD's ability to inhibit apoptosis and to activate Akt and Erk1,2, two EGFR-dependent signaling molecules. Finally, the TCDD-dependent increase in TGFalpha mRNA was also suppressed by MNF. MNF's effects on TCDD action in the MCF-10A cell line occurred at concentrations ranging from 1 nM for Akt phosphorylation and TGFalpha expression to 100 nM for inhibition of apoptosis. Attenuation of TCDD-dependent luciferase activity occurred at concentrations as low as 10 nM, which suggests that TCDD inhibits apoptosis in human mammary epithelial cells by multiple mechanisms.