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

Simko,Veronika; Takacova,Martina; Debreova,Michaela; Laposova,Katarina; Ondriskova-Panisova,Elena; Pastorekova,Silvia; Csaderova,Lucia; Pastorek,Jaromir

doi:10.3892/ijo.2016.3621

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

Authors:
- Veronika Simko
- Martina Takacova
- Michaela Debreova
- Katarina Laposova
- Elena Ondriskova-Panisova
- Silvia Pastorekova
- Lucia Csaderova
- Jaromir Pastorek
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Affiliations: Institute of Virology, Biomedical Research Center, Slovak Academy of Sciences, Bratislava, Slovak Republic
Published online on: July 14, 2016 https://doi.org/10.3892/ijo.2016.3621
Pages: 1277-1288
Copyright: © Simko et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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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.

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