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.
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.
Davis
John W
JW
Toxicology Program, The University of New Mexico College of Pharmacy, Albuquerque, NM 87131, USA. john.davis4@ spcorp.com
Burdick
Andrew D
AD
Lauer
Fredine T
FT
Burchiel
Scott W
SW
D017209:Apoptosis / Q000187:drug effects*; D002460:Cell Line; D004847:Epithelial Cells / Q000187:drug effects / Q000378:metabolism; D066246:ErbB Receptors / Q000378:metabolism; D005419:Flavonoids / Q000494:pharmacology*; D006801:Humans; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D010766:Phosphorylation; D000072317:Polychlorinated Dibenzodioxins / Q000633:toxicity*; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D018336:Receptors, Aryl Hydrocarbon / Q000037:antagonists & inhibitors*; D015398:Signal Transduction / Q000187:drug effects*; D016211:Transforming Growth Factor alpha / Q000096:biosynthesis*
C091768:3'-methoxy-4'-nitroflavone; D005419:Flavonoids; D000072317:Polychlorinated Dibenzodioxins; D011518:Proto-Oncogene Proteins; D018336:Receptors, Aryl Hydrocarbon; D016211:Transforming Growth Factor alpha; D066246:ErbB Receptors; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases