Interaction of 2,3,7,8-tetrachlorodibenzo-p-dioxin, 12-O-tetradecanoylphorbol-13-acetate (TPA) and 17 beta-estradiol in MCF-7 human breast cancer cells.
2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) and 12-O-tetradecanoylphorbol-13-acetate (TPA) are both tumor promoters which act through different mechanisms. In MCF-7 human breast cancer cells, both TCDD and TPA inhibited constitutive and 17 beta-estradiol-induced cell proliferation but showed no apparent interactive effects. TCDD also inhibited the 17 beta-estradiol-induced secretion of the 52-kDa protein (procathepsin D) and induced CYP1A1 gene expression whereas TPA alone was inactive for these responses. Moreover, TPA did not modulate the TCDD-mediated antiestrogenic or induction responses and did not decrease levels of the nuclear Ah receptor complex as determined in a gel mobility shift assay using a 32P-dioxin responsive element (DRE). The interactions of TPA and TCDD on the metabolism of [13C]glucose to [13C]lactate was also investigated using 13C-nuclear magnetic resonance spectroscopy. The rate of formation of [13C]lactate from [13C]glucose in MCF-7 cells treated with DMSO (control), 1 nM 17 beta-estradiol, 1 nM TCDD, 1 nM TCDD plus 1 nM 17 beta-estradiol, and 0.1 ng/ml TPA plus 1 nM 17 beta-estradiol was 28, 48, 20, 22 and 50 fmol lactate formed/cell/h, respectively. Thus, TCDD, but not TPA, inhibited this estrogen-induced response. However, a comparison of the rate of lactate formation in cells treated with TCDD plus 17 beta-estradiol (22 fmol/cell/h) or TCDD plus 17 beta-estradiol plus TPA (61 fmol/cell/h) showed that TPA significantly inhibited the TCDD-mediated antiestrogenic response. The results of these studies in MCF-7 cells demonstrate that the interactions of TCDD and TPA are highly response-specific and do not involve TPA-mediated downregulation of the nuclear Ah receptor complex.
Department of Veterinary Physiology and Pharmacology, Texas A&M University, College Station 77843-4466.
M
M
Moore
T R
TR
Narasimhan
X
X
Wang
V
V
Krishnan
S
S
Safe
H J
HJ
Williams
A I
AI
Scott
D001483:Base Sequence; D001943:Breast Neoplasms / Q000378:metabolism* / Q000473:pathology*; D002402:Cathepsin D / Q000378:metabolism; D002455:Cell Division / Q000187:drug effects; D019363:Cytochrome P-450 CYP1A1; D003577:Cytochrome P-450 Enzyme System / Q000378:metabolism; D004347:Drug Interactions; D004792:Enzyme Precursors / Q000378:metabolism; D004958:Estradiol / Q000494:pharmacology*; D015870:Gene Expression / Q000187:drug effects; D005947:Glucose / Q000378:metabolism; D006801:Humans; D007700:Kinetics; D007773:Lactates / Q000378:metabolism; D019344:Lactic Acid; D009682:Magnetic Resonance Spectroscopy; D008969:Molecular Sequence Data; D010088:Oxidoreductases / Q000378:metabolism; D000072317:Polychlorinated Dibenzodioxins / Q000494:pharmacology*; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug / Q000187:drug effects / Q000378:metabolism; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D004792:Enzyme Precursors; D007773:Lactates; D000072317:Polychlorinated Dibenzodioxins; D018336:Receptors, Aryl Hydrocarbon; D011955:Receptors, Drug; D019344:Lactic Acid; D004958:Estradiol; D003577:Cytochrome P-450 Enzyme System; D010088:Oxidoreductases; D019363:Cytochrome P-450 CYP1A1; C058345:procathepsin D; D002402:Cathepsin D; D005947:Glucose; D013755:Tetradecanoylphorbol Acetate