Comparative Effect of 2,3,7,8-Tetrachlorodibenzo-p-dioxin on MCF-7, PL95-2, and LNCaP Cells: Role of Target Steroid Hormones in Cellular Responsiveness to CYP1A1 Induction

摘要

A study was conducted to investigate whether target hormones affect 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-inducible gene expression, using as an exper-imental model system three human cancer cell lines, breast (MCF-7), uterine (RL95-2), and prostate (LNCaP). Exposure to TCDD induced the CYPlAl gene in all three cell lines. MCF-7 and RL95-2 cells showed more than 15- and 10-fold induction of EROD (7-ethoxyresorufin O-deethylase) activity, respectively, compared with the less responsive LNCaP cells. Sur-prisingly, however, TCDD-induced reporter gene ac-tivity driven by a single XRE element was similar in RL95-2 and LNCaP cells. The steady-state levels of expression of aryl hydrocarbon receptor (AhR) and aryl hydrocarbon receptor nuclear translocator (ARNT) were similar in all three cell lines. Expression of the CYPiBi and PAI-2 genes was induced by TCDD in MCF-7 and RL95-2, but not in LNCaP, cells. Tran-sient coexpression of estradiol receptor-a (ER-a) with a TCDD-responsive reporter plasmid and subsequent TCDD treatment increased responsiveness to TCDD in RL95-2 and LNCaP cells. Treatment with AZA-C, a DNA methyltransferase inhibitor, enhanced respon-siveness to TCDD, in terms of EROD activity in LNCaP cells, but not in MCF-7 and RL95-2 cells, suggesting that DNA methylation in the CpG dinucleotide within the XRE core sequence is another factor involved in silencing of CYPlAl in LNCaP cells. TCDD markedly inhibited EROD activity in the three cell lines.These findings suggest that TCDD and the target steroid hormones negatively regulate each other's activity.