2011
Hrubá, Eva; Vondráček, Jan; Líbalová, Helena; Topinka, Jan; Bryja, Vítězslav; Souček, Karel; Machala, Miroslav
Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands. Journal Article
In: Toxicology letters, vol. 206, no. 2, pp. 178–188, 2011, ISSN: 1879-3169 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Aryl Hydrocarbon/*agonists, Benzo(a)pyrene/*toxicity, Carcinogens, Carcinoma/metabolism, Cell Cycle/drug effects, Cell Line, DNA Repair/drug effects, DNA Replication/drug effects, Environmental/*toxicity, Gene Expression Profiling, Gene Expression Regulation, Humans, Ligands, Male, Mutagens/*toxicity, Neoplastic/*drug effects, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins/*toxicity, Prostatic Neoplasms/*metabolism, Proto-Oncogene Proteins/genetics/metabolism, Receptors, Spindle Apparatus/drug effects, Time Factors, Tumor, Wnt Proteins/genetics/metabolism, Wnt-5a Protein
@article{hruba_gene_2011,
title = {Gene expression changes in human prostate carcinoma cells exposed to genotoxic and nongenotoxic aryl hydrocarbon receptor ligands.},
author = {Eva Hrubá and Jan Vondráček and Helena Líbalová and Jan Topinka and Vítězslav Bryja and Karel Souček and Miroslav Machala},
doi = {10.1016/j.toxlet.2011.07.011},
issn = {1879-3169 0378-4274},
year = {2011},
date = {2011-10-01},
journal = {Toxicology letters},
volume = {206},
number = {2},
pages = {178–188},
abstract = {Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are known as efficient mutagens and ligands of the aryl hydrocarbon receptor (AhR), which has been suggested to play an important role in prostate carcinogenesis. In order to evaluate the complex relationship between the genotoxicity and the AhR-mediated activity of PAHs in prostate cells, we selected benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as model genotoxic and nongenotoxic AhR ligands, respectively, to explore global changes in gene expression in LNCaP cells by microarray analysis. We identified 112 genes that were differentially expressed in cells treated for 24h with BaP, TCDD or both compounds. Our data indicated that the impacts of BaP and TCDD on transcriptome of LNCaP cells significantly overlap, since over 64% of significantly up-regulated genes and 47% of down-regulated genes were similarly affected by both AhR ligands. This suggested that the activation of AhR played a prominent role in the nongenotoxic effects of BaP in the prostate carcinoma cell model LNCaP. Both AhR ligands suppressed expression of genes associated with cell cycle progression, DNA replication, spindle assembly checkpoint or DNA repair, which probably occurred secondary to inhibition of cell cycle progression. In contrast, we identified Wnt5a, an important regulator of prostate cancer progression, to be induced as early as 6h after exposure to both AhR ligands. The AhR ligand-induced Wnt5a upregulation, together with other observed alterations of gene expression, may further contribute to enhanced cell plasticity of prostate carcinoma cells.},
note = {Place: Netherlands},
keywords = {Aryl Hydrocarbon/*agonists, Benzo(a)pyrene/*toxicity, Carcinogens, Carcinoma/metabolism, Cell Cycle/drug effects, Cell Line, DNA Repair/drug effects, DNA Replication/drug effects, Environmental/*toxicity, Gene Expression Profiling, Gene Expression Regulation, Humans, Ligands, Male, Mutagens/*toxicity, Neoplastic/*drug effects, Oligonucleotide Array Sequence Analysis, Polychlorinated Dibenzodioxins/*toxicity, Prostatic Neoplasms/*metabolism, Proto-Oncogene Proteins/genetics/metabolism, Receptors, Spindle Apparatus/drug effects, Time Factors, Tumor, Wnt Proteins/genetics/metabolism, Wnt-5a Protein},
pubstate = {published},
tppubtype = {article}
}
Carcinogenic polycyclic aromatic hydrocarbons (PAHs) are known as efficient mutagens and ligands of the aryl hydrocarbon receptor (AhR), which has been suggested to play an important role in prostate carcinogenesis. In order to evaluate the complex relationship between the genotoxicity and the AhR-mediated activity of PAHs in prostate cells, we selected benzo[a]pyrene (BaP) and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), as model genotoxic and nongenotoxic AhR ligands, respectively, to explore global changes in gene expression in LNCaP cells by microarray analysis. We identified 112 genes that were differentially expressed in cells treated for 24h with BaP, TCDD or both compounds. Our data indicated that the impacts of BaP and TCDD on transcriptome of LNCaP cells significantly overlap, since over 64% of significantly up-regulated genes and 47% of down-regulated genes were similarly affected by both AhR ligands. This suggested that the activation of AhR played a prominent role in the nongenotoxic effects of BaP in the prostate carcinoma cell model LNCaP. Both AhR ligands suppressed expression of genes associated with cell cycle progression, DNA replication, spindle assembly checkpoint or DNA repair, which probably occurred secondary to inhibition of cell cycle progression. In contrast, we identified Wnt5a, an important regulator of prostate cancer progression, to be induced as early as 6h after exposure to both AhR ligands. The AhR ligand-induced Wnt5a upregulation, together with other observed alterations of gene expression, may further contribute to enhanced cell plasticity of prostate carcinoma cells.
2010
Hrubá, Eva; Trilecová, Lenka; Marvanová, Sona; Krcmár, Pavel; Vykopalová, Lenka; Milcová, Alena; Líbalová, Helena; Topinka, Jan; Starsíchová, Andrea; Soucek, Karel; Vondrácek, Jan; Machala, Miroslav
In: Toxicology letters, vol. 197, no. 3, pp. 227–235, 2010, ISSN: 1879-3169 0378-4274, (Place: Netherlands).
Abstract | Links | BibTeX | Tags: Animals, Apoptosis/*drug effects, Carcinoma/*metabolism, Cell Line, DNA Damage/*drug effects, Environmental Pollutants/toxicity, Gene Expression Regulation, Male, Neoplastic/drug effects, Polycyclic Aromatic Hydrocarbons/*toxicity, Prostatic Neoplasms/*metabolism, Tumor, Tumor Suppressor Protein p53/*metabolism
@article{hruba_genotoxic_2010,
title = {Genotoxic polycyclic aromatic hydrocarbons fail to induce the p53-dependent DNA damage response, apoptosis or cell-cycle arrest in human prostate carcinoma LNCaP cells.},
author = {Eva Hrubá and Lenka Trilecová and Sona Marvanová and Pavel Krcmár and Lenka Vykopalová and Alena Milcová and Helena Líbalová and Jan Topinka and Andrea Starsíchová and Karel Soucek and Jan Vondrácek and Miroslav Machala},
doi = {10.1016/j.toxlet.2010.06.004},
issn = {1879-3169 0378-4274},
year = {2010},
date = {2010-09-01},
journal = {Toxicology letters},
volume = {197},
number = {3},
pages = {227–235},
abstract = {Exposure to polycyclic aromatic hydrocarbons (PAHs) has been positively associated with prostate cancer, but knowledge of the formation of PAH-DNA adducts and related genotoxic events in prostatic cells is limited. In the present study, benzo[a]pyrene (BaP), a potent mutagenic PAH, formed significant levels of DNA adducts in cell lines derived from human prostate carcinoma. When analyzing the effect of BaP on the induction of CYP1 enzymes participating in the metabolic activation of PAHs in LNCaP cells, we found that BaP induced expression of CYP1A1 and CYP1A2, but not CYP1B1 enzyme. Despite a significant amount of DNA adducts being formed by BaP and, to a lesser extent also by another strong genotoxin, dibenzo[a,l]pyrene, neither apoptosis nor cell-cycle arrest were induced in LNCaP cells. LNCaP cells were not sensitized to the induction of apoptosis by PAHs even through inhibition of the phosphoinositide-3-kinase/Akt pro-survival pathway. The lack of apoptosis was not due a disruption of expression of pro-apoptotic and pro-survival members of the Bcl-2 family of apoptosis regulators. In contrast to other genotoxic stimuli, genotoxic PAHs failed to induce DNA double-strand breaks, as illustrated by the lack of phosphorylation of histone H2AX or checkpoint kinase-2. BaP did not activate p53, as evidenced by the lack of p53 accumulation, phosphorylation at Ser15, or induction of p53 transcriptional targets. Taken together, although genotoxic PAHs produced significant levels of DNA adducts in a model of human prostate carcinoma cells, they did not activate the mechanisms leading to elimination of cells with significant damage to DNA, presumably due to their failure to activate the p53-dependent DNA damage response.},
note = {Place: Netherlands},
keywords = {Animals, Apoptosis/*drug effects, Carcinoma/*metabolism, Cell Line, DNA Damage/*drug effects, Environmental Pollutants/toxicity, Gene Expression Regulation, Male, Neoplastic/drug effects, Polycyclic Aromatic Hydrocarbons/*toxicity, Prostatic Neoplasms/*metabolism, Tumor, Tumor Suppressor Protein p53/*metabolism},
pubstate = {published},
tppubtype = {article}
}
Exposure to polycyclic aromatic hydrocarbons (PAHs) has been positively associated with prostate cancer, but knowledge of the formation of PAH-DNA adducts and related genotoxic events in prostatic cells is limited. In the present study, benzo[a]pyrene (BaP), a potent mutagenic PAH, formed significant levels of DNA adducts in cell lines derived from human prostate carcinoma. When analyzing the effect of BaP on the induction of CYP1 enzymes participating in the metabolic activation of PAHs in LNCaP cells, we found that BaP induced expression of CYP1A1 and CYP1A2, but not CYP1B1 enzyme. Despite a significant amount of DNA adducts being formed by BaP and, to a lesser extent also by another strong genotoxin, dibenzo[a,l]pyrene, neither apoptosis nor cell-cycle arrest were induced in LNCaP cells. LNCaP cells were not sensitized to the induction of apoptosis by PAHs even through inhibition of the phosphoinositide-3-kinase/Akt pro-survival pathway. The lack of apoptosis was not due a disruption of expression of pro-apoptotic and pro-survival members of the Bcl-2 family of apoptosis regulators. In contrast to other genotoxic stimuli, genotoxic PAHs failed to induce DNA double-strand breaks, as illustrated by the lack of phosphorylation of histone H2AX or checkpoint kinase-2. BaP did not activate p53, as evidenced by the lack of p53 accumulation, phosphorylation at Ser15, or induction of p53 transcriptional targets. Taken together, although genotoxic PAHs produced significant levels of DNA adducts in a model of human prostate carcinoma cells, they did not activate the mechanisms leading to elimination of cells with significant damage to DNA, presumably due to their failure to activate the p53-dependent DNA damage response.