Differentiation‐associated urothelial cytochrome P450 oxidoreductase predicates the xenobiotic‐metabolizing activity of “luminal” muscle‐invasive bladder cancers
Year: 2018
Type: article
Abstract: Extra‐hepatic metabolism of xenobiotics by epithelial tissues has evolved as a self‐defence mechanism but has potential to contribute to the local activation of carcinogens. Bladder epithelium (urothelium) is bathed in excreted urinary toxicants and pro‐carcinogens. This study reveals how differentiation affects cytochrome P450 (CYP) activity and the role of NADPH:P450 oxidoreductase (POR). CYP1A1 and CYP1B1 transcripts were inducible in normal human urothelial (NHU) cells maintained in both undifferentiated and functional barrier‐forming differentiated states in vitro. However, ethoxyresorufin O‐deethylation (EROD) activity, the generation of reactive BaP metabolites and BaP‐DNA adducts, were predominantly detected in differentiated NHU cell cultures. This gain‐of‐function was attributable to the expression of POR, an essential electron donor for all CYPs, which was significantly upregulated as part of urothelial differentiation. Immunohistology of muscle‐invasive bladder cancer (MIBC) revealed significant overall suppression of POR expression. Stratification of MIBC biopsies into “luminal” and “basal” groups, based on GATA3 and cytokeratin 5/6 labeling, showed POR over‐expression by a subgroup of the differentiated luminal tumors. In bladder cancer cell lines, CYP1‐activity was undetectable/low in basal PORlo T24 and SCaBER cells and higher in the luminal POR over‐expressing RT4 and RT112 cells than in differentiated NHU cells, indicating that CYP‐function is related to differentiation status in bladder cancers. This study establishes POR as a predictive biomarker of metabolic potential. This has implications in bladder carcinogenesis for the hepatic versus local activation of carcinogens and as a functional predictor of the potential for MIBC to respond to prodrug therapies.
Source: Molecular Carcinogenesis
DOI: 10.1002/mc.22784
Language: English
Subfield: Pharmacology
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $2,618
Funders: Univerzita Karlova v Praze, Wellcome Trust, Astellas European Foundation, National Institute for Health Research Health Protection Research Unit, Cancer Research UK, National Institute for Health and Care Research, Royal Society, King's College London, Grantová Agentura České Republiky, Public Health England, Astellas Pharma, Natural Environment Research Council
Awards: G204274736, Value in people award., Mutational signatures of DNA damage and repair processes., G3413721157, G3483115772, Mutational signatures of DNA damage and repair processes., Construction of modified apoferritin nanocarriers bearing anticancer drugs and study of mechanisms enhancing their efficiency in anticancer therapy, Institutional Strategic Support Fund Phase2 FY2014/16, G5610406756, Elucidating the potential interaction of manufactured nanoparticles with polycyclic aromatic hydrocarbons: An integrated toxicogenomics approach, G5921254298, G6016606592, G6197456947
OpenAlex ID: W2783525627