Husbeck Bryan, Powis Garth
Arizona Cancer Center, University of Arizona, 1515 N. Campbell Avenue, Tucson, AZ 85724-5024, USA.
Carcinogenesis. 2002 Oct;23(10):1625-30. doi: 10.1093/carcin/23.10.1625.
The oxidative metabolites of estrogen have been proposed to play an important role in the development of some human cancers. The two major pathways of estrogen metabolism, to the carcinogenic 4-hydroxyestradiol (4-OHE2) and to the non-carcinogenic 2-hydroxyestradiol (2-OHE2), are mediated by cytochromes P450 CYP1B1 and CYP1A1, respectively. The expression of CYP1A1 and CYP1B1 is regulated by the aromatic hydrocarbon receptor/Ah receptor nuclear translocator (AhR/ARNT) transcription factor complex. CYP1B1 expression is elevated in a wide range of human cancers but is not found in corresponding normal tissue. Thioredoxin-1 (Trx-1) is a small redox protein that is overexpressed in a number of human cancers. We report that the expression of CYP1B1 mRNA and protein is increased by Trx-1 transfection of MCF-7 human breast cancer cells and decreased by a redox inactive mutant Trx-1. The Trx-1 inhibitor PX-12 inhibits CYP1B1 gene expression. Trx-1 transfected MCF-7 cells show increased AhR/ARNT DNA binding activity that is not due to altered AhR or ARNT protein expression. 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD, dioxin) induced expression of CYP1B1 in MCF-7 cells is increased by Trx-1. Trx-1 does not effect the basal expression of CYP1A1, but increases CYP1A1 mRNA in response to TCDD. The redox inactive mutant Trx-1 completely blocks the induction of both CYP1B1 and CYP1A1 by TCDD. Expression of CYP1A1 but not CYP1B1 has been linked to estrogen receptor (ERalpha) status. Trx-1 transfected MCF-7 cells have decreased ERalpha expression, which may account for the lack of CYP1A1 induction by Trx-1 in the absence of ligand. The results suggest that Trx-1 is involved in the constitutive expression of CYP1B1 and is required for the induction of CYP1B1 and CYP1A1 by TCDD in human MCF-7 breast cancer cells.
雌激素的氧化代谢产物被认为在某些人类癌症的发展中起重要作用。雌激素代谢的两条主要途径，分别生成致癌性的4-羟基雌二醇（4-OHE2）和非致癌性的2-羟基雌二醇（2-OHE2），分别由细胞色素P450 CYP1B1和CYP1A1介导。CYP1A1和CYP1B1的表达受芳烃受体/芳烃受体核转运蛋白（AhR/ARNT）转录因子复合物调控。CYP1B1在多种人类癌症中表达升高，但在相应的正常组织中未发现。硫氧还蛋白-1（Trx-1）是一种小的氧化还原蛋白，在多种人类癌症中过度表达。我们报告，通过MCF-7人乳腺癌细胞的Trx-1转染，CYP1B1 mRNA和蛋白的表达增加，而氧化还原无活性的突变型Trx-1则使其降低。Trx-1抑制剂PX-12抑制CYP1B1基因表达。Trx-1转染的MCF-7细胞显示AhR/ARNT DNA结合活性增加，这并非由于AhR或ARNT蛋白表达改变所致。2,3,7,8-四氯二苯并对二恶英（TCDD，二恶英）诱导的MCF-7细胞中CYP1B1的表达因Trx-1而增加。Trx-1不影响CYP1A1的基础表达，但在TCDD刺激下增加CYP1A1 mRNA。氧化还原无活性的突变型Trx-1完全阻断TCDD对CYP1B1和CYP1A1的诱导。CYP1A1而非CYP1B1的表达与雌激素受体（ERα）状态有关。Trx-1转染的MCF-7细胞中ERα表达降低，这可能解释了在无配体情况下Trx-1对CYP1A1诱导的缺乏。结果表明，Trx-1参与CYP1B1的组成性表达，并且是TCDD诱导人MCF-7乳腺癌细胞中CYP1B1和CYP1A1所必需的。
