Latest Publications

@article{umannova_benzopyrene_2011,

title = {Benzo[a]pyrene and tumor necrosis factor-α coordinately increase genotoxic damage and the production of proinflammatory mediators in alveolar epithelial type II cells.},

author = {Lenka Umannová and Miroslav Machala and Jan Topinka and Jana Schmuczerová and Pavel Krčmář and Jiří Neča and Klára Šujanová and Alois Kozubík and Jan Vondráček},

doi = {10.1016/j.toxlet.2011.06.029},

issn = {1879-3169 0378-4274},

year  = {2011},

date = {2011-10-01},

journal = {Toxicology letters},

volume = {206},

number = {2},

pages = {121–129},

abstract = {Alveolar type II epithelial (AEII) cells regulate lung inflammatory response and, simultaneously, they are a target of environmental carcinogenic factors. We employed an in vitro model of rat AEII cells, the RLE-6TN cell line, in order to analyze the interactive effects of tumor necrosis factor-α (TNF-α), a cytokine which plays a key role in the initiation of inflammatory responses in the lung, and benzo[a]pyrene (BaP), a highly carcinogenic polycyclic aromatic hydrocarbon. TNF-α strongly augmented the formation of stable BaP diol epoxide-DNA adducts in AEII cells, which was associated with enhanced p53-Ser15 phosphorylation and decreased cell survival. The increased genotoxicity of BaP was associated with altered expression of cytochrome P450 (CYP) enzymes involved in its bioactivation, a simultaneous suppression of CYP1A1 and enhancement of CYP1B1 expression. Importantly, BaP and TNF-α acted synergistically to upregulate key inflammatory regulators in AEII cells, including the expression of inducible NO synthase and cyclooxygenase-2 (COX-2), and enhanced prostaglandin E2 production and expression of proinflammatory cytokines, such as TNF-α, interleukin-1β and interleukin-6. We observed that BaP and TNF-α together strongly activated p38 kinase, a principal regulator of inflammatory response. SB202190, a specific p38 inhibitor, prevented induction of both COX-2 and proinflammatory cytokines, thus confirming that p38 activity was crucial for the observed inflammatory reaction. Taken together, our data demonstrated, for the first time, that a proinflammatory cytokine and an environmental PAH may interact to potentiate both DNA damage and the inflammatory response in AEII cells, which may occur through coordinated upregulation of p38 activity.},

note = {Place: Netherlands},

keywords = {Alveolar Epithelial Cells/*drug effects/immunology/*metabolism, Animals, Apoptosis/drug effects, Aryl Hydrocarbon Hydroxylases/genetics/metabolism, Benzo(a)pyrene/metabolism/*toxicity, Carcinogens, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 CYP1A1/genetics/metabolism, Cytochrome P-450 CYP1B1, DNA Adducts/*metabolism, Environmental/toxicity, Enzyme Activation/drug effects, Gene Expression Regulation/drug effects, Inflammation Mediators/*metabolism, Messenger/metabolism, Mutagens/*toxicity, p38 Mitogen-Activated Protein Kinases/antagonists & inhibitors/metabolism, Phosphorylation/drug effects, Post-Translational/drug effects, Protein Kinase Inhibitors/pharmacology, Protein Processing, Rats, RNA, Tumor Necrosis Factor-alpha/*metabolism, Tumor Suppressor Protein p53/metabolism},

pubstate = {published},

tppubtype = {article}

}

@article{slabakova_tgf-1-induced_2011,

title = {TGF-β1-induced EMT of non-transformed prostate hyperplasia cells is characterized by early induction of SNAI2/Slug.},

author = {Eva Slabáková and Zuzana Pernicová and Eva Slavíčková and Andrea Staršíchová and Alois Kozubík and Karel Souček},

doi = {10.1002/pros.21350},

issn = {1097-0045 0270-4137},

year  = {2011},

date = {2011-09-01},

journal = {The Prostate},

volume = {71},

number = {12},

pages = {1332–1343},

abstract = {BACKGROUND: Epithelial-mesenchymal transition (EMT) underlying cancer cell invasion and metastasis has been thoroughly studied in prostate cancer. Although EMT markers have been clinically observed in benign prostate hyperplasia, molecular events underlying the onset and progression of EMT in benign prostate cells have not been described. METHODS: EMT in BPH-1 cells was induced by TGF-β1 treatment and the kinetics of expression of EMT markers, regulators, and selected miRNAs was assessed by western blotting and quantitative RT-PCR. RESULTS: EMT in BPH-1 cells was accompanied by rapid up-regulation of SNAI2/Slug and ZEB1 transcription factors, while changes in expression levels of ZEB2 and miR-200 family members were observed after extended time intervals. Invasive phenotype with EMT hallmarks, characterizing tumorigenic clones derived from BPH-1 cells, was associated with increased mRNA levels of SNAI2, ZEB1, and ZEB2, but was not associated with significant changes in basal levels of miR-200 family members. RNA interference revealed that SNAI2/Slug is crucial for TGF-β1-induced vimentin up-regulation and migration of BPH-1 cells. CONCLUSIONS: This study suggests that in BPH-1 cells the transcription factor SNAI2/Slug is important for EMT initiation, while the ZEB family of transcription factors in cooperation with the miR-200 family may oppose the reversal of the EMT phenotype.},

note = {Place: United States},

keywords = {*Epithelial-Mesenchymal Transition/genetics, Biomarkers/metabolism, Cell Line, Cell Movement, Homeodomain Proteins/genetics, Humans, Kinetics, Male, Messenger/metabolism, MicroRNAs/metabolism, Neoplasm Invasiveness/genetics, Phenotype, Prostatic Hyperplasia/*physiopathology, Repressor Proteins/genetics, RNA, Snail Family Transcription Factors, Transcription Factors/*biosynthesis/genetics, Transforming Growth Factor beta1/*pharmacology, Up-Regulation/drug effects, Vimentin/metabolism, Zinc Finger E-box Binding Homeobox 2, Zinc Finger E-box-Binding Homeobox 1},

pubstate = {published},

tppubtype = {article}

}

@article{marvanova_toxic_2008,

title = {Toxic effects of methylated benz[a]anthracenes in liver cells.},

author = {Sona Marvanová and Jan Vondrácek and Katerrina Penccíková and Lenka Trilecová and Pavel Krcmárr and Jan Topinka and Zuzana Nováková and Alena Milcová and Miroslav Machala},

doi = {10.1021/tx700305x},

issn = {0893-228X},

year  = {2008},

date = {2008-02-01},

journal = {Chemical research in toxicology},

volume = {21},

number = {2},

pages = {503–512},

abstract = {Monomethylated benz[ a]anthracenes (MeBaAs) are an important group of methylated derivatives of polycyclic aromatic hydrocarbons (PAHs). Although the methyl substitution reportedly affects their mutagenicity and tumor-initiating activity, little is known about the impact of methylation on the effects associated with activation of the aryl hydrocarbon receptor (AhR)-dependent gene expression and/or toxic events associated with tumor promotion. In the present study, we studied the effects of a series of MeBaAs on the above-mentioned end points in rat liver cell lines and compared them with the effects of benz[ a]anthracene (BaA) and the potent carcinogen 7,12-dimethylbenz[ a]anthracene (DMBA). Methyl substitution enhanced the AhR-mediated activity of BaA derivatives determined in a reporter gene assay, as the induction equivalency factors (IEFs) of all MeBaAs were higher than that of BaA. IEFs of 6-MeBaA and 9-MeBaA, two of the most potent MeBaAs, were more than two orders of magnitude higher than the IEF of BaA. Correspondingly, all MeBaAs induced higher levels of cytochrome P450 1A1 mRNA. Both BaA and MeBaAs had similar effects on the expression of cytochrome P450 1B1 or aldo-keto reductase 1C9 in rat liver epithelial WB-F344 cells. In contrast to genotoxic DMBA, MeBaAs induced low DNA adduct formation. Only 10-MeBaA induced apoptosis and accumulation of phosphorylated p53, which could be associated with the induction of oxidative stress, similar to DMBA. With the exception of 10-MeBaA, all MeBaAs induced cell proliferation in contact-inhibited WB-F344 cells, which corresponded with their ability to activate AhR. 1-, 2-, 8-, 10-, 11-, and 12-MeBaA inhibited gap junctional intercellular communication (GJIC) in WB-F344 cells. This mode of action, like disruption of cell proliferation control, might contribute to tumor promotion. Taken together, these data showed that the methyl substitution significantly influences those effects of MeBaAs associated with AhR activation or GJIC inhibition.},

note = {Place: United States},

keywords = {10-Dimethyl-1, 2-benzanthracene/chemistry/metabolism/toxicity, 9, Animals, Apoptosis/drug effects, Benz(a)Anthracenes/chemistry/metabolism/*toxicity, Carcinoma, Cell Line, Cell Proliferation/drug effects, Cytochrome P-450 Enzyme System/genetics/metabolism, DNA Adducts/analysis/metabolism, DNA/drug effects/metabolism, Dose-Response Relationship, Drug, Enzyme Induction, Enzymologic/drug effects, Gap Junctions/drug effects, Gene Expression Regulation, Genes, Hepatocellular, Hepatocytes/*drug effects/metabolism/pathology, Inbred F344, Liver Neoplasms, Messenger/metabolism, Methylation, Rats, Reporter/drug effects, RNA, Stem Cells/*drug effects/metabolism/pathology, Tumor},

pubstate = {published},

tppubtype = {article}

}