Dexamethasone downregulates expression of carbonic anhydrase IX via HIF-1α and NF-κB-dependent mechanisms

• Published in: International journal of oncology Vol. 49; no. 4; pp. 1277 - 1288
• Main Authors: Simko, Veronika, Takacova, Martina, Debreova, Michaela, Laposova, Katarina, Ondriskova-Panisova, Elena, Pastorekova, Silvia, Csaderova, Lucia, Pastorek, Jaromir
• Format: Journal Article
• Language: English
• Published: Greece D.A. Spandidos 01.10.2016; Spandidos Publications; Spandidos Publications UK Ltd
• Subjects: Analysis; Angiogenesis; Antigens, Neoplasm - genetics; Antigens, Neoplasm - metabolism; Apoptosis; Binding Sites; Brain cancer; Breast cancer; Cancer; Cancer therapies; carbonic anhydrase IX; Carbonic Anhydrase IX - genetics; Carbonic Anhydrase IX - metabolism; Care and treatment; Cell cycle; Cell Hypoxia - drug effects; Cell Line, Tumor; Cell Proliferation - drug effects; Chemotherapy; Cytokines; Dexamethasone; Dexamethasone - pharmacology; Dose-Response Relationship, Drug; Down-Regulation; Enzymes; Gene expression; Glucocorticoids - pharmacology; Health aspects; Hematology; Humans; Hypoxia; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; hypoxia-inducible factor-1α; Inflammation; Kinases; Lung cancer; MCF-7 Cells; Medical prognosis; NF-kappa B - metabolism; nuclear factor-kappaB; Patient outcomes; Phosphorylation; Promoter Regions, Genetic; Properties; Proteins; Radiation therapy; Spheroids, Cellular - drug effects; Spheroids, Cellular - pathology; Steroids; Transcription factors; transcriptional regulation; Tumors
• ISSN: 1019-6439; 1791-2423
• DOI: 10.3892/ijo.2016.3621

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 dexa-methasone treatment and implication of additional regulatory mechanisms can be relevant for the CA IX-related clinical applications.