Characterization of anti-apoptotic action of TCDD as a defensive cellular stress response reaction against the cell damaging action of ultra-violet irradiation in an immortalized normal human mammary epithelial cell line, MCF10A.
It was originally shown by Woerner and Schrenk [Woerner, W., Schrenk, D., 1998. 2,3,7,8-Tetrachlorodibenzo-p-dioxin suppresses apoptosis and leads to hyperphosphorylation of p53 in rat hepatocytes. Environ. Toxicol. Pharmacol. 6, 239-247] that TCDD (2,3,7,8-tetrachlorodibenzo-p-dioxin) acts as an antagonist against the action of UV-irradiation to induce apoptosis in rat primary hepatocytes. Since prevention of apoptosis has been shown to promote carcinogenesis, we have decided to investigate this phenomenon in a human mammary gland epithelial cell line, MCF10A. We found that, in this cell line, TCDD can antagonize apoptosis that was induced by a variety of treatments, such as UV- and gamma-irradiation, growth factor starvation and trypsinization, or by the addition of H(2)O(2), TGFbeta, and staurosporine. Furthermore, other agents that are known to elicit defensive cellular responses, such as LPS, Fe(3+), nitric oxide and hypoxia could also antagonize UV induced apoptosis just as in the case of TCDD. In addition, we found that, in this cell line, such anti-apoptotic action of TCDD resembles that of exogenously added EGF or TGF alpha. To study the basic mechanism of such an action of TCDD, we tested a variety of diagnostic agents to reverse the effect of TCDD. Antagonists of TCDD which were found to be effective in this way were (a) inhibitors of c-Src kinase, such as PP-2 and CGP77675, (b) those known to block the action of TGF alpha, such as anti-TGF alpha antibody, and alpha(1)-antitrypsin, (c) PD98059, a specific inhibitor of ERK activation, but not SB202190 (an inhibitor of p38 MAPK activation) or SP600125 (a JNK inhibitor) and (d) Ah receptor antagonists, alpha-naphthoflavone and 1, 10-phenanthroline. These results support the notion that TCDD acts as an anti-apoptotic agent by mimicking the action of EGF through activation of the c-Src/ERK signaling pathway.
Park
Sujin
S
Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA 95616, USA.
Matsumura
Fumio
F
D000222:Adaptation, Physiological / Q000187:drug effects; D017209:Apoptosis / Q000187:drug effects*; D001571:Benzoflavones / Q000494:pharmacology; D002070:Butadienes / Q000494:pharmacology; D002460:Cell Line; D053938:DNA Fragmentation / Q000187:drug effects; D004815:Epidermal Growth Factor / Q000494:pharmacology; D004847:Epithelial Cells / Q000187:drug effects / Q000528:radiation effects; D005260:Female; D005290:Ferric Compounds / Q000494:pharmacology; D005419:Flavonoids / Q000494:pharmacology; D005978:Glutathione / Q000031:analogs & derivatives / Q000494:pharmacology; D006801:Humans; D006861:Hydrogen Peroxide / Q000633:toxicity; D008070:Lipopolysaccharides / Q000494:pharmacology; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009570:Nitriles / Q000494:pharmacology; D009574:Nitro Compounds / Q000494:pharmacology; D010618:Phenanthrolines / Q000494:pharmacology; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D011743:Pyrimidines / Q000494:pharmacology; D011758:Pyrroles / Q000494:pharmacology; D000644:Quaternary Ammonium Compounds / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016211:Transforming Growth Factor alpha / Q000494:pharmacology; D014466:Ultraviolet Rays; D000515:alpha 1-Antitrypsin / Q000494:pharmacology; D051028:bcl-2-Associated X Protein / Q000235:genetics / Q000378:metabolism
C412373:AG 1879; D001571:Benzoflavones; D002070:Butadienes; D005290:Ferric Compounds; D005419:Flavonoids; D008070:Lipopolysaccharides; D009570:Nitriles; D009574:Nitro Compounds; D010618:Phenanthrolines; D000072317:Polychlorinated Dibenzodioxins; D011743:Pyrimidines; D011758:Pyrroles; D000644:Quaternary Ammonium Compounds; D012333:RNA, Messenger; C116027:S-nitroglutathione; D016211:Transforming Growth Factor alpha; C113580:U 0126; D000515:alpha 1-Antitrypsin; D051028:bcl-2-Associated X Protein; C011512:alpha-naphthoflavone; D004815:Epidermal Growth Factor; D006861:Hydrogen Peroxide; D020928:Mitogen-Activated Protein Kinases; C119957:CGP 77675; D005978:Glutathione; C093973:2-(2-amino-3-methoxyphenyl)-4H-1-benzopyran-4-one; C013531:ferric ammonium citrate; C025205:1,10-phenanthroline