Deregulation of signaling pathways controlling cell survival and proliferation in cancer cells alters induction of cytochrome P450 family 1 enzymes
Language English Country Ireland Media print-electronic
Document type Journal Article, Research Support, Non-U.S. Gov't
PubMed
34403729
DOI
10.1016/j.tox.2021.152897
PII: S0300-483X(21)00220-1
Knihovny.cz E-resources
- Keywords
- AhR, CYP1 enzymes, Cancer cells, Cell proliferation, p300, β-Catenin signaling,
- MeSH
- Cytochrome P-450 CYP1A1 biosynthesis genetics MeSH
- Enzyme Induction physiology MeSH
- HCT116 Cells MeSH
- Liver pathology MeSH
- Humans MeSH
- Cell Line, Tumor MeSH
- Colonic Neoplasms genetics pathology MeSH
- Cell Proliferation physiology MeSH
- E1A-Associated p300 Protein metabolism MeSH
- Gene Expression Regulation, Neoplastic MeSH
- Hippo Signaling Pathway physiology MeSH
- Wnt Signaling Pathway physiology MeSH
- Signal Transduction physiology MeSH
- Cell Survival physiology MeSH
- Check Tag
- Humans MeSH
- Publication type
- Journal Article MeSH
- Research Support, Non-U.S. Gov't MeSH
- Names of Substances
- CYP1A1 protein, human MeSH Browser
- Cytochrome P-450 CYP1A1 MeSH
- EP300 protein, human MeSH Browser
- E1A-Associated p300 Protein MeSH
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.
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