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

Novel fluorinated carbonic anhydrase IX inhibitors reduce hypoxia-induced acidification and clonogenic survival of cancer cells

“…Tumor hypoxia promotes invasiveness and is associated with resistance to chemotherapeutics and radiation and thus poor prognosis [ 1 – 5 ]. Human carbonic anhydrase IX (CA IX) shows limited expression in normal tissues [ 6 ] and is significantly up-regulated by hypoxia-inducible factor 1α (HIF-1α) [ 7 ] or other alternative microenvironmental factors [ 8 – 12 ] in a variety of tumors. CA IX is crucial for cancer cell survival because bicarbonate and protons, produced upon CA IX-catalyzed reversible hydration of CO 2 , are necessary to maintain the cellular pH balance: bicarbonate is transported into the cell to neutralize intracellular acid, while protons increase extracellular acidification [ 13 – 16 ].…”

Hypoxia Preconditioning of Human MSCs: a Direct Evidence of HIF-1α and Collagen Type XV Correlation

“…Consequently, the limited stability of HIF-1α could mask its effective role in hMSCs during a prolonged biological process, such as osteogenic terminal differentiation. Moreover, even if the interplay between glucocorticoid and HIF-1α in hypoxic areas remains unclear, many evidences demonstrated that dexamethasone reduces protein level of HIF-1α as well as its activity affecting transcription of HIF-1α target genes [50,51]. Therefore, we cannot exclude that long-term hypoxic treatment in vitro can lead to results that are difficult to explain when hMSCs are induced to differentiate toward the osteogenic lineage by the conventional dexamethasone-added osteogenic medium.…”

Diallyl disulfide inhibits the metastasis of type Ⅱ esophageal‑gastric junction adenocarcinoma cells via NF-κB and PI3K/AKT signaling pathways in vitro

“…Degradation of IκB leads to the activation of the pathway, resulting in the nuclear translocation of the NF-κB complexes (32). In the nucleus, activated NF-κB binds to the specific DnA sequence called response element in the promoter region of a number of target genes including cytokines, chemokines, adhesion molecules as well as angiogenic factors and key enzymes, and subsequently regulates tumor initiation and progression (33). The promotion of NF-κB pathway increases the metastatic activity of cancer cells by upregulating u-PA and MMPs (34).…”