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@article{1232054,
author = {Kabátková, Markéta and Zapletal, Ondřej and Tylichová, Zuzana and Neča, Jiří and Machala, Miroslav and Milcova, A. and Topinka, J. and Kozubík, Alois and Vondráček, Jan},
article_location = {OXFORD},
article_number = {4},
doi = {http://dx.doi.org/10.1093/mutage/gev019},
keywords = {ARYL-HYDROCARBON RECEPTOR; POLYCYCLIC AROMATIC-HYDROCARBONS; COLORECTAL-CANCER; EPITHELIAL-CELLS; IN-VITRO; GENE-EXPRESSION; METABOLIC-ACTIVATION; APC(MIN) MUTATION; PATHWAY; WNT},
language = {eng},
issn = {0267-8357},
journal = {MUTAGENESIS},
title = {Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation},
url = {http://mutage.oxfordjournals.org/content/early/2015/03/24/mutage.gev019.long},
volume = {30},
year = {2015}
}
TY - JOUR
ID - 1232054
AU - Kabátková, Markéta - Zapletal, Ondřej - Tylichová, Zuzana - Neča, Jiří - Machala, Miroslav - Milcova, A. - Topinka, J. - Kozubík, Alois - Vondráček, Jan
PY - 2015
TI - Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation
JF - MUTAGENESIS
VL - 30
IS - 4
SP - 565-576
EP - 565-576
PB - OXFORD UNIV PRESS
SN - 02678357
KW - ARYL-HYDROCARBON RECEPTOR
KW - POLYCYCLIC AROMATIC-HYDROCARBONS
KW - COLORECTAL-CANCER
KW - EPITHELIAL-CELLS
KW - IN-VITRO
KW - GENE-EXPRESSION
KW - METABOLIC-ACTIVATION
KW - APC(MIN) MUTATION
KW - PATHWAY
KW - WNT
UR - http://mutage.oxfordjournals.org/content/early/2015/03/24/mutage.gev019.long
L2 - http://mutage.oxfordjournals.org/content/early/2015/03/24/mutage.gev019.long
N2 - 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.
ER -
KABÁTKOVÁ, Markéta, Ondřej ZAPLETAL, Zuzana TYLICHOVÁ, Jiří NEČA, Miroslav MACHALA, A. MILCOVA, J. TOPINKA, Alois KOZUBÍK and Jan VONDRÁČEK. Inhibition of beta-catenin signalling promotes DNA damage elicited by benzo[a]pyrene in a model of human colon cancer cells via CYP1 deregulation. \textit{MUTAGENESIS}. OXFORD: OXFORD UNIV PRESS, 2015, vol.~30, No~4, p.~565-576. ISSN~0267-8357. Available from: https://dx.doi.org/10.1093/mutage/gev019.
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