Detailed Information on Publication Record
2015
Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation
KABÁTKOVÁ, Markéta, Ondřej ZAPLETAL, Zuzana TYLICHOVÁ, Jiří NEČA, Miroslav MACHALA et. al.Basic information
Original name
Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation
Authors
KABÁTKOVÁ, Markéta (203 Czech Republic, belonging to the institution), Ondřej ZAPLETAL (203 Czech Republic, belonging to the institution), Zuzana TYLICHOVÁ (203 Czech Republic, belonging to the institution), Jiří NEČA (203 Czech Republic), Miroslav MACHALA (203 Czech Republic), A. MILCOVA (203 Czech Republic), J. TOPINKA (203 Czech Republic), Alois KOZUBÍK (203 Czech Republic) and Jan VONDRÁČEK (203 Czech Republic, guarantor)
Edition
MUTAGENESIS, OXFORD, OXFORD UNIV PRESS, 2015, 0267-8357
Other information
Language
English
Type of outcome
Článek v odborném periodiku
Field of Study
10608 Biochemistry and molecular biology
Country of publisher
United Kingdom of Great Britain and Northern Ireland
Confidentiality degree
není předmětem státního či obchodního tajemství
References:
Impact factor
Impact factor: 2.297
RIV identification code
RIV/00216224:14310/15:00095774
Organization unit
Faculty of Science
UT WoS
000357885900012
Keywords in English
ARYL-HYDROCARBON RECEPTOR; POLYCYCLIC AROMATIC-HYDROCARBONS; COLORECTAL-CANCER; EPITHELIAL-CELLS; IN-VITRO; GENE-EXPRESSION; METABOLIC-ACTIVATION; APC(MIN) MUTATION; PATHWAY; WNT
Tags
International impact, Reviewed
Změněno: 13/4/2018 15:42, Ing. Nicole Zrilić
Abstract
V originále
Deregulation of Wnt/beta-catenin signalling plays an important role in the pathogenesis of colorectal cancer. Interestingly, this pathway has been recently implicated in transcriptional control of cytochrome P450 (CYP) family 1 enzymes, which are responsible for bioactivation of a number of dietary carcinogens. In the present study, we investigated the impact of inhibition of Wnt/beta-catenin pathway on metabolism and genotoxicity of benzo[a]pyrene (BaP), a highly mutagenic polycyclic aromatic hydrocarbon and an efficient ligand of the aryl hydrocarbon receptor, which is known as a primary regulator of CYP1 expression, in cellular models derived from colorectal tumours. We observed that a synthetic inhibitor of beta-catenin, JW74, significantly increased formation of BaP-induced DNA adducts in both colorectal adenoma and carcinoma-derived cell lines. Using the short interfering RNA (siRNA) targeting beta-catenin, we then found that beta-catenin knockdown in HCT116 colon carcinoma cells significantly enhanced formation of covalent DNA adducts by BaP and histone H2AX phosphorylation, as detected by P-32-postlabelling technique and immunocytochemistry, respectively, and it also induced expression of DNA damage response genes, such as CDKN1A or DDB2. The increased formation of DNA adducts formed by BaP upon beta-catenin knockdown corresponded with enhanced production of major BaP metabolites, as well as with an increased expression/activity of CYP1 enzymes. Finally, using siRNA-mediated knockdown of CYP1A1, we confirmed that this enzyme plays a major role in formation of BaP-induced DNA adducts in HCT116 cells. Taken together, the present results indicated that the siRNA-mediated inhibition of beta-catenin signalling, which is aberrantly activated in a majority of colorectal cancers, modulated genotoxicity of dietary carcinogen BaP in colon cell model in vitro, via a mechanism involving up-regulation of CYP1 expression and activity.