کد مقاله | کد نشریه | سال انتشار | مقاله انگلیسی | نسخه تمام متن |
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2598005 | 1562439 | 2006 | 8 صفحه PDF | دانلود رایگان |

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 H2O2, TGFβ, and staurosporine. Furthermore, other agents that are known to elicit defensive cellular responses, such as LPS, Fe3+, 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 TGFα. 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 TGFα, such as anti-TGFα antibody, and α1-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, α-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.
Journal: Toxicology - Volume 217, Issues 2–3, 16 January 2006, Pages 139–146