Park Sujin, Matsumura Fumio
Department of Environmental Toxicology, University of California, One Shields Avenue, Davis, CA 95616, USA.
Toxicology. 2006 Jan 16;217(2-3):139-46. doi: 10.1016/j.tox.2005.09.002. Epub 2005 Oct 6.
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.
最初，沃纳和施伦克[沃纳，W.，施伦克，D.，1998年。2,3,7,8-四氯二苯并对二恶英抑制大鼠肝细胞凋亡并导致p53过度磷酸化。环境毒理学与药理学。6，239 - 247]表明，TCDD（2,3,7,8-四氯二苯并对二恶英）作为紫外线照射诱导大鼠原代肝细胞凋亡作用的拮抗剂。由于已证明预防细胞凋亡会促进致癌作用，我们决定在人乳腺上皮细胞系MCF10A中研究这一现象。我们发现，在该细胞系中，TCDD可拮抗由多种处理诱导的细胞凋亡，如紫外线和γ射线照射、生长因子饥饿和胰蛋白酶消化，或通过添加H₂O₂、TGFβ和星形孢菌素诱导的细胞凋亡。此外，其他已知能引发细胞防御反应的物质，如LPS、Fe³⁺、一氧化氮和缺氧，也能像TCDD一样拮抗紫外线诱导的细胞凋亡。另外，我们发现，在该细胞系中，TCDD的这种抗凋亡作用类似于外源性添加的EGF或TGFα的作用。为了研究TCDD这种作用的基本机制，我们测试了多种诊断试剂以逆转TCDD的作用。以这种方式发现有效的TCDD拮抗剂有：（a）c-Src激酶抑制剂，如PP-2和CGP77675；（b）已知能阻断TGFα作用的物质，如抗TGFα抗体和α₁-抗胰蛋白酶；（c）PD98059，一种ERK激活的特异性抑制剂，但不是SB202190（p38 MAPK激活抑制剂）或SP600125（JNK抑制剂）；（d）Ah受体拮抗剂α-萘黄酮和1,10-菲咯啉。这些结果支持了这样一种观点，即TCDD通过激活c-Src/ERK信号通路模拟EGF的作用，从而作为一种抗凋亡剂发挥作用。
