2007
Umannová, Lenka; Zatloukalová, Jirina; Machala, Miroslav; Krcmár, Pavel; Májková, Zuzana; Hennig, Bernhard; Kozubík, Alois; Vondrácek, Jan
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 99, no. 1, pp. 79–89, 2007, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Animals, Aryl Hydrocarbon Hydroxylases/genetics/*metabolism, Aryl Hydrocarbon/*drug effects/metabolism, Carcinogens/metabolism/toxicity, Cell Proliferation/drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Enzymologic/*drug effects, Epithelial Cells/drug effects/enzymology, Gene Expression Regulation, Inbred F344, Ligands, Liver/cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Polychlorinated Dibenzodioxins/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology, Tumor Necrosis Factor-alpha/*pharmacology
@article{umannova_tumor_2007,
title = {Tumor necrosis factor-alpha modulates effects of aryl hydrocarbon receptor ligands on cell proliferation and expression of cytochrome P450 enzymes in rat liver "stem-like" cells.},
author = {Lenka Umannová and Jirina Zatloukalová and Miroslav Machala and Pavel Krcmár and Zuzana Májková and Bernhard Hennig and Alois Kozubík and Jan Vondrácek},
doi = {10.1093/toxsci/kfm149},
issn = {1096-6080 1096-0929},
year = {2007},
date = {2007-09-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {99},
number = {1},
pages = {79–89},
abstract = {Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-alpha with ligands of the aryl hydrocarbon receptor (AhR) and known liver carcinogens, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126). These compounds have been previously found to disrupt cell cycle control in contact-inhibited rat liver WB-F344 cells, an in vitro model of adult liver progenitor cells. TNF-alpha itself had no significant effect on the proliferation/apoptosis ratio in the WB-F344 cell line. However, it significantly potentiated proliferative effects of low picomolar range doses of both TCDD and PCB 126, leading to an increase in cell numbers, as well as an increased percentage of cells entering the S-phase of the cell cycle. The combination of TNF-alpha with low concentrations of AhR ligands increased both messenger RNA (mRNA) and protein levels of cyclin A, a principle cyclin involved in disruption of contact inhibition. TNF-alpha temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-alpha significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-kappaB activation. These results suggest that TNF-alpha can significantly amplify effects of AhR ligands on deregulation of cell proliferation control, as well as on expression of CYP1B1, which is involved in metabolic activation of a number of mutagenic compounds.},
note = {Place: United States},
keywords = {Animals, Aryl Hydrocarbon Hydroxylases/genetics/*metabolism, Aryl Hydrocarbon/*drug effects/metabolism, Carcinogens/metabolism/toxicity, Cell Proliferation/drug effects, Cells, Cultured, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, Dose-Response Relationship, Drug, Drug Combinations, Drug Interactions, Enzymologic/*drug effects, Epithelial Cells/drug effects/enzymology, Gene Expression Regulation, Inbred F344, Ligands, Liver/cytology, Polychlorinated Biphenyls/metabolism/*toxicity, Polychlorinated Dibenzodioxins/metabolism/*toxicity, Rats, Receptors, Stem Cells/*drug effects/enzymology, Tumor Necrosis Factor-alpha/*pharmacology},
pubstate = {published},
tppubtype = {article}
}
Various liver diseases lead to an extensive inflammatory response and release of a number of proinflammatory cytokines, such as tumor necrosis factor-alpha (TNF-alpha). This cytokine is known to play a major role in liver regeneration as well as in carcinogenesis. We investigated possible interactions of TNF-alpha with ligands of the aryl hydrocarbon receptor (AhR) and known liver carcinogens, such as 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) and coplanar 3,3',4,4',5-pentachlorobiphenyl (PCB 126). These compounds have been previously found to disrupt cell cycle control in contact-inhibited rat liver WB-F344 cells, an in vitro model of adult liver progenitor cells. TNF-alpha itself had no significant effect on the proliferation/apoptosis ratio in the WB-F344 cell line. However, it significantly potentiated proliferative effects of low picomolar range doses of both TCDD and PCB 126, leading to an increase in cell numbers, as well as an increased percentage of cells entering the S-phase of the cell cycle. The combination of TNF-alpha with low concentrations of AhR ligands increased both messenger RNA (mRNA) and protein levels of cyclin A, a principle cyclin involved in disruption of contact inhibition. TNF-alpha temporarily inhibited AhR-dependent induction of cytochrome P450 1A1 (CYP1A1). In contrast, TNF-alpha significantly enhanced induction of CYP1B1 at both mRNA and protein levels, by a mechanism, which was independent of nuclear factor-kappaB activation. These results suggest that TNF-alpha can significantly amplify effects of AhR ligands on deregulation of cell proliferation control, as well as on expression of CYP1B1, which is involved in metabolic activation of a number of mutagenic compounds.
2005
Plísková, Martina; Vondrácek, Jan; Vojtesek, Borivoj; Kozubík, Alois; Machala, Miroslav
In: Toxicological sciences : an official journal of the Society of Toxicology, vol. 83, no. 2, pp. 246–256, 2005, ISSN: 1096-6080 1096-0929, (Place: United States).
Abstract | Links | BibTeX | Tags: Benz(a)Anthracenes/*toxicity, Benzo(a)pyrene/*toxicity, Benzothiazoles, Breast Neoplasms/drug therapy/*genetics/metabolism, Bromodeoxyuridine/metabolism, Carcinogens/*toxicity, Carcinoma/drug therapy/*genetics/metabolism, Cell Cycle/drug effects, Cell Line, Cell Proliferation/*drug effects, Cell Survival/drug effects, DNA Replication/drug effects, Dose-Response Relationship, Drug, Drug Interactions, Epigenesis, Estradiol/*analogs & derivatives/pharmacology, Estrogen, Estrogen Antagonists/pharmacology, Female, Fulvestrant, Genetic, Humans, Receptors, Thiazoles/pharmacology, Toluene/*analogs & derivatives/pharmacology, Tumor, Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/metabolism
@article{pliskova_deregulation_2005,
title = {Deregulation of cell proliferation by polycyclic aromatic hydrocarbons in human breast carcinoma MCF-7 cells reflects both genotoxic and nongenotoxic events.},
author = {Martina Plísková and Jan Vondrácek and Borivoj Vojtesek and Alois Kozubík and Miroslav Machala},
doi = {10.1093/toxsci/kfi040},
issn = {1096-6080 1096-0929},
year = {2005},
date = {2005-02-01},
journal = {Toxicological sciences : an official journal of the Society of Toxicology},
volume = {83},
number = {2},
pages = {246–256},
abstract = {Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are carcinogens suggested to be involved in development of human cancer. Several recent studies have reported that PAHs can activate estrogen receptors (ER), either directly or indirectly by producing estrogenic metabolites. We hypothesized that the activation of ER by PAHs or their metabolites could induce cell proliferation in estrogen-sensitive cells. In the present study, we found that two PAHs, benz[a]anthracene (BaA) and BaP, can stimulate proliferation of human breast carcinoma MCF-7 cells at concentrations 100 nM and higher. This effect was ER-dependent, because it was blocked by the pure antiestrogen ICI 182,780. Although both PAHs partially inhibited S-phase entry and DNA synthesis induced by 17beta-estradiol, they stimulated S-phase entry when applied to MCF-7 cells synchronized by serum deprivation. This was in contrast with model antiestrogenic aryl hydrocarbon receptor ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which fully suppressed S-phase entry. BaP, which is a strong mutagen, was found to induce p53 tumor suppressor expression, a partial S-phase arrest and at higher concentrations also cell death. Pifithrin-alpha, a synthetic inhibitor of p53 activity, abolished both S-phase arrest and apoptosis induced by genotoxic PAHs, and it potentiated the proliferative effect of BaP. Thus, both genotoxic and nongenotoxic events seem to interact in the effects of BaP on cell proliferation. Taken together, our data indicate that both BaA and BaP can stimulate cell proliferation through activation of ER. The proliferative effects of these carcinogenic compounds might contribute to tumor promotion in estrogen-sensitive tissues.},
note = {Place: United States},
keywords = {Benz(a)Anthracenes/*toxicity, Benzo(a)pyrene/*toxicity, Benzothiazoles, Breast Neoplasms/drug therapy/*genetics/metabolism, Bromodeoxyuridine/metabolism, Carcinogens/*toxicity, Carcinoma/drug therapy/*genetics/metabolism, Cell Cycle/drug effects, Cell Line, Cell Proliferation/*drug effects, Cell Survival/drug effects, DNA Replication/drug effects, Dose-Response Relationship, Drug, Drug Interactions, Epigenesis, Estradiol/*analogs & derivatives/pharmacology, Estrogen, Estrogen Antagonists/pharmacology, Female, Fulvestrant, Genetic, Humans, Receptors, Thiazoles/pharmacology, Toluene/*analogs & derivatives/pharmacology, Tumor, Tumor Suppressor Protein p53/antagonists & inhibitors/genetics/metabolism},
pubstate = {published},
tppubtype = {article}
}
Polycyclic aromatic hydrocarbons (PAHs), such as benzo[a]pyrene (BaP), are carcinogens suggested to be involved in development of human cancer. Several recent studies have reported that PAHs can activate estrogen receptors (ER), either directly or indirectly by producing estrogenic metabolites. We hypothesized that the activation of ER by PAHs or their metabolites could induce cell proliferation in estrogen-sensitive cells. In the present study, we found that two PAHs, benz[a]anthracene (BaA) and BaP, can stimulate proliferation of human breast carcinoma MCF-7 cells at concentrations 100 nM and higher. This effect was ER-dependent, because it was blocked by the pure antiestrogen ICI 182,780. Although both PAHs partially inhibited S-phase entry and DNA synthesis induced by 17beta-estradiol, they stimulated S-phase entry when applied to MCF-7 cells synchronized by serum deprivation. This was in contrast with model antiestrogenic aryl hydrocarbon receptor ligand, 2,3,7,8-tetrachlorodibenzo-p-dioxin, which fully suppressed S-phase entry. BaP, which is a strong mutagen, was found to induce p53 tumor suppressor expression, a partial S-phase arrest and at higher concentrations also cell death. Pifithrin-alpha, a synthetic inhibitor of p53 activity, abolished both S-phase arrest and apoptosis induced by genotoxic PAHs, and it potentiated the proliferative effect of BaP. Thus, both genotoxic and nongenotoxic events seem to interact in the effects of BaP on cell proliferation. Taken together, our data indicate that both BaA and BaP can stimulate cell proliferation through activation of ER. The proliferative effects of these carcinogenic compounds might contribute to tumor promotion in estrogen-sensitive tissues.