Laboratory of Veterinary Biochemistry and Immunology, College of Veterinary Medicine, Chungbuk National University, Cheongju, Chungbuk 361-763, Republic of Korea.
Toxicology. 2013 Feb 8;304:13-20. doi: 10.1016/j.tox.2012.10.012. Epub 2012 Dec 3.
Endocrine disrupting chemicals (EDCs) are defined as environmental compounds that modulate steroid hormone receptor-dependent responses an abnormal manner, resulting in adverse health problems for humans such as cancer growth and metastasis. Cathepsins are proteases that have been implicated in cancer progression. However, there have been few studies about the association between cathepsins and estrogenic chemicals during the cancer progression. In this study, we examined the effect(s) of 4-tert-octylphenol (OP), a potent EDC, on the expression of cathepsins B and D in human MCF-7 breast cancer cells and a xenograft mouse model. Treatment with OP significantly induced the proliferation MCF-7 cells in an MTT assay. In addition, the expression of cathepsins B and D was markedly enhanced in MCF-7 cells at both the transcriptional and the translational levels following treatment with E2 or OP up to 48h. These results demonstrated the ability of OP to disrupt normal transcriptional regulation of cathepsins B and D in human breast cancer cells. However, the effects of OP on cell growth or overexpression of cathepsins by inhibiting ER-mediated signaling were abolished by an ER antagonist and siRNA specific for ERα. In conclusion, our findings suggest that OP at 10(-6)M, like E2, may accelerate breast cancer cell proliferation and the expression of cathepsins through an ER-mediated signaling pathway. In addition, the breast cancer cells exposed with OP to a xenograft mouse model were more aggressive according to our histological analysis and showed markedly increased expression of cathepsin B. These effects of mouse model resulted in an increased potential for metastasis in breast cancer. Taken together, we determined that OP can adversely affect human health by promoting cancer proliferation and metastasis through the amplification of cathepsins B and D via the ER-mediated signaling pathway.
内分泌干扰化学物质 (EDCs) 被定义为以异常方式调节甾体激素受体依赖性反应的环境化合物，导致人类出现癌症生长和转移等不良健康问题。组织蛋白酶是与癌症进展有关的蛋白酶。然而，在癌症进展过程中，关于组织蛋白酶与雌激素类化学物质之间的关联的研究甚少。在这项研究中，我们研究了 4-叔辛基苯酚 (OP)，一种有效的内分泌干扰物，对人 MCF-7 乳腺癌细胞和异种移植小鼠模型中组织蛋白酶 B 和 D 表达的影响。MTT 分析表明，OP 处理可显著诱导 MCF-7 细胞增殖。此外，在 MCF-7 细胞中，用 E2 或 OP 处理高达 48 小时后，组织蛋白酶 B 和 D 的表达在转录和翻译水平上均明显增强。这些结果表明，OP 能够破坏人乳腺癌细胞中组织蛋白酶 B 和 D 的正常转录调节。然而，OP 对细胞生长或通过抑制 ER 介导的信号转导对组织蛋白酶的过表达的影响，被 ER 拮抗剂和针对 ERα 的 siRNA 所消除。总之，我们的研究结果表明，10(-6)M 的 OP 与 E2 一样，可能通过 ER 介导的信号通路加速乳腺癌细胞增殖和组织蛋白酶的表达。此外，根据我们的组织学分析，暴露于 OP 的乳腺癌细胞在异种移植小鼠模型中更具侵袭性，表现出明显增加的组织蛋白酶 B 表达。这些小鼠模型的影响导致乳腺癌转移的潜力增加。总之，我们确定 OP 通过 ER 介导的信号通路放大组织蛋白酶 B 和 D，从而促进癌症增殖和转移，从而对人类健康产生不利影响。
