title: Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms.
abstract: Dexamethasone is a synthetic glucocorticoid frequently used to suppress side-effects of anticancer chemotherapy. In the present study, we showed that dexamethasone treatment leads to concentration-dependent downregulation of cancer-associated marker, carbonic anhydrase IX (CA IX), at the level of promoter activity, mRNA and protein expression in 2D and 3D cancer cell models. The effect of dexamethasone on CA IX expression under hypoxic conditions is predominantly mediated by impaired transcriptional activity and decreased protein level of the main hypoxic transcription factor HIF-1α. In addition, CA9 downregulation can be caused by protein-protein interactions between activated glucocorticoid receptors, major effectors of glucocorticoid action, and transcription factors that trigger CA9 transcription (e.g. AP-1). Moreover, we identified a potential NF-κB binding site in the CA9 promoter and propose the involvement of NF-κB in the dexamethasone-mediated inhibition of CA9 transcription. As high level of CA IX is often linked to aggressive tumor behavior, poor prognosis and chemo- and radiotherapy resistance, uncovering its reduction after dexamethasone treatment and implication of additional regulatory mechanisms can be relevant for the CA IX-related clinical applications.
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Veronika
authors.initials: V
authors.lastname: Simko
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Martina
authors.initials: M
authors.lastname: Takacova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Michaela
authors.initials: M
authors.lastname: Debreova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Katarina
authors.initials: K
authors.lastname: Laposova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Elena
authors.initials: E
authors.lastname: Ondriskova-Panisova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Silvia
authors.initials: S
authors.lastname: Pastorekova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Lucia
authors.initials: L
authors.lastname: Csaderova
authors.affiliation: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic.
authors.forename: Jaromir
authors.initials: J
authors.lastname: Pastorek
mesh_terms: D000951:Antigens, Neoplasm / Q000235:genetics / Q000378:metabolism*; D001665:Binding Sites; D000071231:Carbonic Anhydrase IX / Q000235:genetics / Q000378:metabolism*; D015687:Cell Hypoxia / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D003907:Dexamethasone / Q000494:pharmacology*; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation; D005938:Glucocorticoids / Q000494:pharmacology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism*; D061986:MCF-7 Cells; D016328:NF-kappa B / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D018874:Spheroids, Cellular / Q000187:drug effects / Q000473:pathology
chemical_list: D000951:Antigens, Neoplasm; D005938:Glucocorticoids; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016328:NF-kappa B; D003907:Dexamethasone; C089226:CA9 protein, human; D000071231:Carbonic Anhydrase IX