Latest Publications

@article{paculova_brca1_2017,

title = {BRCA1 or CDK12 loss sensitizes cells to CHK1 inhibitors.},

author = {Hana Paculová and Juraj Kramara and Šárka Šimečková and Radek Fedr and Karel Souček and Ondřej Hylse and Kamil Paruch and Marek Svoboda and Martin Mistrík and Jiří Kohoutek},

doi = {10.1177/1010428317727479},

issn = {1423-0380 1010-4283},

year  = {2017},

date = {2017-10-01},

journal = {Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine},

volume = {39},

number = {10},

pages = {1010428317727479},

abstract = {A broad spectrum of tumors develop resistance to classic chemotherapy, necessitating the discovery of new therapies. One successful strategy exploits the synthetic lethality between poly(ADP-ribose) polymerase 1/2 proteins and DNA damage response genes, including BRCA1, a factor involved in homologous recombination-mediated DNA repair, and CDK12, a transcriptional kinase known to regulate the expression of DDR genes. CHK1 inhibitors have been shown to enhance the anti-cancer effect of DNA-damaging compounds. Since loss of BRCA1 increases replication stress and leads to DNA damage, we tested a hypothesis that CDK12- or BRCA1-depleted cells rely extensively on S-phase-related CHK1 functions for survival. The silencing of BRCA1 or CDK12 sensitized tumor cells to CHK1 inhibitors in vitro and in vivo. BRCA1 downregulation combined with CHK1 inhibition induced excessive amounts of DNA damage, resulting in an inability to complete the S-phase. Therefore, we suggest CHK1 inhibition as a strategy for targeting BRCA1- or CDK12-deficient tumors.},

note = {Place: Netherlands},

keywords = {Animals, BRCA1, BRCA1 Protein/antagonists & inhibitors/*genetics, CDK12, Checkpoint Kinase 1/*genetics, CHK1 inhibitor, Colorectal Neoplasms/drug therapy/*genetics/pathology, Cyclin-Dependent Kinases/antagonists & inhibitors/*genetics, DNA damage response, DNA Damage/drug effects, Drug resistance, Gene Expression Regulation, Gene Silencing, HCT116 Cells, Humans, Mice, Neoplasm/genetics, Neoplastic/drug effects, Poly (ADP-Ribose) Polymerase-1/genetics, Pyrazoles/administration & dosage, Pyrimidines/administration & dosage, Transcription, Xenograft Model Antitumor Assays},

pubstate = {published},

tppubtype = {article}

}

@article{vondracek_role_2009,

title = {The role of aryl hydrocarbon receptor in regulation of enzymes involved in metabolic activation of polycyclic aromatic hydrocarbons in a model of rat liver progenitor cells.},

author = {Jan Vondrácek and Pavel Krcmár and Jirina Procházková and Lenka Trilecová and Martina Gavelová and Lenka Skálová and Barbora Szotáková and Martin Buncek and Hana Radilová and Alois Kozubík and Miroslav Machala},

doi = {10.1016/j.cbi.2009.03.011},

issn = {1872-7786 0009-2797},

year  = {2009},

date = {2009-07-01},

journal = {Chemico-biological interactions},

volume = {180},

number = {2},

pages = {226–237},

abstract = {In contrast to hepatocytes, there is only limited information about the expression and activities of enzymes participating in metabolic activation of environmental mutagens, including polycyclic aromatic hydrocarbons (PAHs), in liver progenitor cells. In rat liver "stem-like" WB-F344 cell line, sharing many characteristics with rat liver progenitor cells, PAHs are efficiently activated to their ultimate genotoxic metabolites forming DNA adducts. The present study aimed to characterize expression/activities of enzymes of two major pathways involved in the metabolism of benzo[a]pyrene (BaP): cytochrome P450 (CYP) family 1 enzymes and cytosolic aldo-keto reductases (AKRs). We report here that, apart from induction of CYP1A1 and CYP1B1 expression and the corresponding enzymatic activity, both BaP and 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) induced rat 3alpha-hydroxysteroid dehydrogenase (AKR1C9) expression and activity. In contrast, the aldehyde reductase AKR1A1 was not induced by either treatment. Thus, both CYP1 and AKR metabolic pathways were inducible in the model of liver progenitor cells. BaP and TCDD were efficient inducers of NAD(P)H:quinone oxidoreductase 1 (NQO1) expression and activity in WB-F344 cells, a principal enzyme of cellular antioxidant defense. Both compounds also induced expression of transcription factor NRF2, involved in control of enzymes protecting cells from oxidative stress. However, although BaP induced a significant formation of reactive oxygen species, it did not induce expression of heme oxygenase-1, suggesting that induction of oxidative stress by BaP was limited. Using shRNA against the aryl hydrocarbon receptor (AhR), we found that similar to CYP1A1 and CYP1B1, the AKR1C9 induction was AhR-dependent. Moreover, constitutive AKR1C9 levels in AhR-deficient rat BP8 hepatoma cells were significantly lower than in their AhR-positive 5L variant, thus supporting possible role of AhR in regulation of AKR1C9 expression. Taken together, both CYP1 and AKR1C9 appear to be AhR-regulated metabolic pathways, which may contribute to formation of pro-carcinogenic PAH metabolites in liver progenitor cells.},

note = {Place: Ireland},

keywords = {Animals, Aryl Hydrocarbon/*metabolism, Benzo(a)pyrene/toxicity, Cell Line, Dimethyl Sulfoxide/toxicity, Enzymologic/drug effects, Gene Expression Regulation, Gene Silencing, Hydrogen Peroxide/toxicity, Liver/*cytology/*enzymology, Polychlorinated Dibenzodioxins/analogs & derivatives/toxicity, Polycyclic Aromatic Hydrocarbons/*metabolism, Rats, Reactive Oxygen Species, Receptors, Stem Cells/*drug effects/*metabolism},

pubstate = {published},

tppubtype = {article}

}