A Dexamethasone-regulated Gene Signature Is Prognostic for Poor Survival in Glioblastoma Patients

Abstract

Background Dexamethasone is reported to induce both tumor-suppressive and tumor-promoting effects. The purpose of this study was to identify the genomic impact of dexamethasone in glioblastoma stem cell (GSC) lines and its prognostic value; furthermore, to identify drugs that can counter these side effects of dexamethasone exposure. Methods We utilized three independent GSC lines with tumorigenic potential for this study. Whole-genome expression profiling and pathway analyses were done with dexamethasone-exposed and control cells. GSCs were also co-exposed to dexamethasone and temozolomide. Risk scores were calculated for most affected genes, and their associations with survival in TCGA and REMBRANDT databases. In silico connectivity Map analysis identified camptothecin as antagonist to dexamethasone induced negative effects. Results Pathway analyses predicted an activation of dexamethasone network (z-score:2.908). Top activated canonical pathways included ‘role of BRCA1 in DNA damage response’ (p=1.07E-04). GSCs were protected against temozolomide-induced apoptosis when co-incubated with dexamethasone. Altered cellular functions included cell-movement, cell-survival, and apoptosis with z-scores of 2.815, 5.137, and −3.122 respectively. CEBPB was activated in a dose dependent manner specifically in slow-dividing ‘stem-like’ cells. CEBPB was activated in dexamethasone-treated orthotopic tumors. Patients with high risk score had significantly shorter survival. Camptothecin was validated as potential partial neutralizer of dexamethasone effects. Conclusions Dexamethasone exposure induces a genetic program and CEBPB expression in GSCs that adversely affects key cellular functions and response to therapeutics. High risk scores associated with these genes have negative prognostic value. Our findings further suggest camptothecin as a potential neutralizer of adverse dexamethasone-mediated effects.

Dopamine D2 receptor antagonist sulpiride enhances dexamethasone responses in the treatment of drug-resistant and metastatic breast cancer

“…The percentage of CSCs in tumors after DEX monotherapy was increased, in agreement with previous studies that demonstrated that treatment by single chemotherapy [42] or anti-angiogenic agents [43,44] may increase the population of CSCs through the generation of tumor hypoxia or other underlying mechanisms. Recently, DEX was found to induce a genetic program and CCAAT/enhancer binding protein beta (CEBPB) expression in glioblastoma stem cells, which is indicative of poor survival in glioblastoma patients [45] . These reported findings might explain why the proportion of CSCs in the DEX-treated group increased and confirm the necessity of the combined use of DEX and anti-CSC agents.…”

Antagonism of Dexamethasone to Radiation Bystander Effect and Its Re-transmission

“…Luedi MM reported that dexamethasone reduced temozolomide-induced apoptosis in glioma stem cells and reduced radiation sensitivity. Camptothecin is a potential neutralizer for dexamethasone-mediated adverse reactions [12]. Ortega-Martínez S has the opposite report in the study of astrocytoma.…”

Dexamethasone-mediated oncogenicity in vitro and in an animal model of glioblastoma

“…11 GBM patient-derived GSCs were cultured as described previously. 9,11,22 In brief, tumors were isolated, followed by enzyme treatment to obtain a single cell suspension that was then cultured in GSC media (DMEM/F12 containing 1× B27, 20 ng/ml EGF, and 20 ng/ml basic fibroblast growth factor). Two independent GSC lines (GSC3 and GSC6) were cultured as neurospheres for further scrutiny.…”

“…For the in vitro studies, we used 50 μM dexamethasone, a concentration that was within the wide range that was previously described for in vitro studies. 1,11 Neurospheres were exposed to Accutase cell detachment solution (EMD Millipore) for 3 minutes to obtain single cells and then cultured in GSC medium containing 50 μM dexamethasone (Sigma) for 6 days or GSC medium alone for the control, with media exchanged daily.…”

“…21,22 GSCs are a reliable tool for recapitulating the disease's biological characteristics. 2 Recently, our in vitro study showed that a dexamethasone-regulated gene signature activates CEBPB expression in GSCs 11 and thus demonstrated that dexamethasone treatment can have adverse implications on the molecular biological characteristics of GBM and on the treatment efficiency conferred by standard-of-care therapy. 27 However, the drug's impact on invasion, proliferation, and angiogenesis in GBM remains unclear.…”