2002
Vondrácek, Jan; Kozubík, Alois; Machala, Miroslav
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 70, no. 2, pp. 193–201, 2002, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Breast Neoplasms/*metabolism, Cell Cycle/*drug effects/genetics, Cell Cycle/drug effects/genetics, Cultured, Estrogen Receptor alpha, Estrogen Receptor Modulators/pharmacology, Estrogen/genetics/*metabolism, G1 Phase/drug effects/genetics, Genes, Genetic/drug effects, Humans, Phosphorylation/drug effects, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter/*genetics, Resting Phase, S Phase/drug effects/genetics, Transcription, Tumor Cells
@article{vondracek_modulation_2002,
title = {Modulation of estrogen receptor-dependent reporter construct activation and G0/G1-S-phase transition by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells.},
author = {Jan Vondrácek and Alois Kozubík and Miroslav Machala},
doi = {10.1093/toxsci/70.2.193},
issn = {1096-6080 1096-0929},
year = {2002},
date = {2002-12-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {70},
number = {2},
pages = {193–201},
abstract = {It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.},
note = {Place: United States},
keywords = {Breast Neoplasms/*metabolism, Cell Cycle/*drug effects/genetics, Cell Cycle/drug effects/genetics, Cultured, Estrogen Receptor alpha, Estrogen Receptor Modulators/pharmacology, Estrogen/genetics/*metabolism, G1 Phase/drug effects/genetics, Genes, Genetic/drug effects, Humans, Phosphorylation/drug effects, Polycyclic Aromatic Hydrocarbons/metabolism/*toxicity, Receptors, Reporter/*genetics, Resting Phase, S Phase/drug effects/genetics, Transcription, Tumor Cells},
pubstate = {published},
tppubtype = {article}
}
It has been suggested that the estrogenicity of PAHs could contribute to their carcinogenic effects via increased tissue-specific cell proliferation. Both benzo[a]pyrene (BaP) and benz[a]anthracene (BaA) are known to weakly activate estrogen receptor (ER)-dependent reporter constructs. In this study, several other PAHs, including fluorene, fluoranthene, pyrene, chrysene, phenanthrene and anthracene, were found to act as very weak inducers of ER-mediated activity in the MCF-7 cell line stably transfected with a luciferase reporter gene. The effects of PAHs were time-dependent and they were not completely inhibited by antiestrogen ICI 182,780. In addition, BaP and BaA, as well as weakly estrogenic fluoranthene, significantly potentiated the maximum ER-mediated activity of 17beta-estradiol. Therefore, the effects of inhibitors of several types of protein kinases known to activate ERalpha in a ligand-independent manner were investigated. However, neither inhibitors nor inducers of extracellular signal-regulated kinases 1 and 2 (ERK1/2), phosphatidylinositol-3 kinase, protein kinase C, c-Src, or protein kinase A modified ER-mediated activity in this model. Neither estradiol nor BaA activated ERK1/2, two kinases suggested to play significant roles in ER signaling, suggesting that another kinase is involved in the observed phosphorylation of ERalpha. Similar to 17beta-estradiol, BaA stimulated G(0)/G(1)-S-phase transition in MCF-7 cells, which was fully suppressed by ICI 182,780. In conclusion, some PAHs can potentiate 17beta-estradiol-induced ER activation and stimulate cell cycle entry in vitro. However, their exact mode(s) of action and whether this phenomenon is of in vivo relevance remains to be elucidated.