2021
Krkoška, Martin; Svobodová, Jana; Kabátková, Markéta; Zapletal, Ondřej; Vaculová, Alena Hyršlová; Nekvindová, Jana; Vondráček, Jan
In: Toxicology, vol. 461, pp. 152897, 2021, ISSN: 1879-3185 0300-483X, (Place: Ireland).
Abstract | Links | BibTeX | Tags: AhR, Cancer cells, Cell Line, Cell Proliferation, Cell Proliferation/*physiology, Cell Survival/physiology, Colonic Neoplasms/genetics/*pathology, CYP1 enzymes, Cytochrome P-450 CYP1A1/biosynthesis/*genetics, E1A-Associated p300 Protein/metabolism, Enzyme Induction/physiology, Gene Expression Regulation, HCT116 Cells, Hippo Signaling Pathway/physiology, Humans, Liver/*pathology, Neoplastic, p300, Signal Transduction/physiology, Tumor, Wnt Signaling Pathway/physiology, β-Catenin signaling
@article{krkoska_deregulation_2021,
title = {Deregulation of signaling pathways controlling cell survival and proliferation in cancer cells alters induction of cytochrome P450 family 1 enzymes.},
author = {Martin Krkoška and Jana Svobodová and Markéta Kabátková and Ondřej Zapletal and Alena Hyršlová Vaculová and Jana Nekvindová and Jan Vondráček},
doi = {10.1016/j.tox.2021.152897},
issn = {1879-3185 0300-483X},
year = {2021},
date = {2021-09-01},
journal = {Toxicology},
volume = {461},
pages = {152897},
abstract = {Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.},
note = {Place: Ireland},
keywords = {AhR, Cancer cells, Cell Line, Cell Proliferation, Cell Proliferation/*physiology, Cell Survival/physiology, Colonic Neoplasms/genetics/*pathology, CYP1 enzymes, Cytochrome P-450 CYP1A1/biosynthesis/*genetics, E1A-Associated p300 Protein/metabolism, Enzyme Induction/physiology, Gene Expression Regulation, HCT116 Cells, Hippo Signaling Pathway/physiology, Humans, Liver/*pathology, Neoplastic, p300, Signal Transduction/physiology, Tumor, Wnt Signaling Pathway/physiology, β-Catenin signaling},
pubstate = {published},
tppubtype = {article}
}
Cytochrome P450 family 1 (CYP1) enzymes contribute both to metabolism of xenobiotics and to the control of endogenous levels of ligands of the aryl hydrocarbon receptor (AhR). Their activities, similar to other CYPs, can be altered in tumor tissues. Here, we examined a possible role of proliferative/survival pathways signaling, which is often deregulated in tumor cells, and possible links with p300 histone acetyltransferase (a transcriptional co-activator) in the control of CYP1 expression, focusing particularly on CYP1A1. Using cell models derived from human liver, we observed that the induction of CYP1A1 expression, as well as other CYP1 enzymes, was reduced in exponentially growing cells, as compared with their non-dividing counterparts. The siRNA-mediated inhibition of proliferation/pro-survival signaling pathway effectors (such as β-catenin and/or Hippo pathway effectors YAP/TAZ) increased the AhR ligand-induced CYP1A1 mRNA levels in liver HepaRG cells, and/or in colon carcinoma HCT-116 cells. The activation of proliferative Wnt/β-catenin signaling in HCT-116 cells reduced both the induction of CYP1 enzymes and the binding of p300 to the promoter of CYP1A1 or CYP1B1 genes. These results seem to indicate that aberrant proliferative signaling in tumor cells could suppress induction of CYP1A1 (or other CYP1 enzymes) via competition for p300 binding. This mechanism could be involved in modulation of the metabolism of both endogenous and exogenous substrates of CYP1A1 (and other CYP1 enzymes), with possible further consequences for alterations of the AhR signaling in tumor cells, or additional functional roles of CYP1 enzymes.
2015
Pálková, Lenka; Vondráček, Jan; Trilecová, Lenka; Ciganek, Miroslav; Pěnčíková, Kateřina; Neča, Jiří; Milcová, Alena; Topinka, Jan; Machala, Miroslav
In: Toxicology in vitro : an international journal published in association with BIBRA, vol. 29, no. 3, pp. 438–448, 2015, ISSN: 1879-3177 0887-2333, (Place: England).
Abstract | Links | BibTeX | Tags: Air Pollutants/*toxicity, Air pollution, Animals, Apoptosis, Apoptosis/drug effects, Aryl Hydrocarbon/*drug effects, Cell Cycle/drug effects, Cell Death/drug effects, Cell Proliferation, DNA adducts, DNA Damage, DNA damage response, Liver/*pathology, Lung/*pathology, Male, Mutagens/*toxicity, PAHs, Particulate Matter/*toxicity, Prostate/*pathology, Rats, Receptors, SRM 1650b, Vehicle Emissions/*toxicity
@article{palkova_aryl_2015,
title = {The aryl hydrocarbon receptor-mediated and genotoxic effects of fractionated extract of standard reference diesel exhaust particle material in pulmonary, liver and prostate cells.},
author = {Lenka Pálková and Jan Vondráček and Lenka Trilecová and Miroslav Ciganek and Kateřina Pěnčíková and Jiří Neča and Alena Milcová and Jan Topinka and Miroslav Machala},
doi = {10.1016/j.tiv.2014.12.002},
issn = {1879-3177 0887-2333},
year = {2015},
date = {2015-04-01},
journal = {Toxicology in vitro : an international journal published in association with BIBRA},
volume = {29},
number = {3},
pages = {438–448},
abstract = {Diesel exhaust particles (DEP) and the associated complex mixtures of organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), or their derivatives, have been suggested to exert deleterious effects on human health. We used a set of defined cellular models representing liver, lung and prostate tissues, in order to compare non-genotoxic and genotoxic effects of crude and fractionated extract of a standard reference DEP material - SRM 1650b. We focused on the aryl hydrocarbon receptor (AhR)-mediated activity, modulation of cell proliferation, formation of DNA adducts, oxidative DNA damage, and induction of DNA damage responses, including evaluation of apoptosis, and phosphorylation of p53 tumor suppressor and checkpoint kinases (Chk). Both PAHs and the polar aromatic compounds contributed to the AhR-mediated activity of DEP-associated organic pollutants. The principal identified AhR agonists included benzo[k]fluoranthene, indeno[1,2,3-c,d]pyrene, chrysene and several non-priority PAHs, including benzochrysenes and methylated PAHs. In contrast to PAHs, polar compounds contributed more significantly to overall formation of DNA adducts associated with phosphorylation of p53, Chk1 or Chk2, and partly with apoptosis. Therefore, more attention should be paid to identification of DEP-associated polar organic compounds, contributing to the AhR activation and cytotoxic/genotoxic effects of complex airborne mixtures of organic contaminants produced by diesel engines.},
note = {Place: England},
keywords = {Air Pollutants/*toxicity, Air pollution, Animals, Apoptosis, Apoptosis/drug effects, Aryl Hydrocarbon/*drug effects, Cell Cycle/drug effects, Cell Death/drug effects, Cell Proliferation, DNA adducts, DNA Damage, DNA damage response, Liver/*pathology, Lung/*pathology, Male, Mutagens/*toxicity, PAHs, Particulate Matter/*toxicity, Prostate/*pathology, Rats, Receptors, SRM 1650b, Vehicle Emissions/*toxicity},
pubstate = {published},
tppubtype = {article}
}
Diesel exhaust particles (DEP) and the associated complex mixtures of organic pollutants, such as polycyclic aromatic hydrocarbons (PAHs), or their derivatives, have been suggested to exert deleterious effects on human health. We used a set of defined cellular models representing liver, lung and prostate tissues, in order to compare non-genotoxic and genotoxic effects of crude and fractionated extract of a standard reference DEP material - SRM 1650b. We focused on the aryl hydrocarbon receptor (AhR)-mediated activity, modulation of cell proliferation, formation of DNA adducts, oxidative DNA damage, and induction of DNA damage responses, including evaluation of apoptosis, and phosphorylation of p53 tumor suppressor and checkpoint kinases (Chk). Both PAHs and the polar aromatic compounds contributed to the AhR-mediated activity of DEP-associated organic pollutants. The principal identified AhR agonists included benzo[k]fluoranthene, indeno[1,2,3-c,d]pyrene, chrysene and several non-priority PAHs, including benzochrysenes and methylated PAHs. In contrast to PAHs, polar compounds contributed more significantly to overall formation of DNA adducts associated with phosphorylation of p53, Chk1 or Chk2, and partly with apoptosis. Therefore, more attention should be paid to identification of DEP-associated polar organic compounds, contributing to the AhR activation and cytotoxic/genotoxic effects of complex airborne mixtures of organic contaminants produced by diesel engines.