Dexamethasone mediates pancreatic cancer progression by glucocorticoid receptor, TGFβ and JNK/AP-1

Abstract

Glucocorticoids such as dexamethasone are widely co-prescribed with cytotoxic therapy because of their proapoptotic effects in lymphoid cancer, reduction of inflammation and edema and additional benefits. Concerns about glucocorticoid-induced therapy resistance, enhanced metastasis and reduced survival of patients are largely not considered. We analyzed dexamethasone-induced tumor progression in three established and one primary human pancreatic ductal adenocarcinoma (PDA) cell lines and in PDA tissue from patients and xenografts by FACS and western blot analysis, immunohistochemistry, MTT and wound assay, colony and spheroid formation, EMSA and in vivo tumor growth and metastasis of tumor xenografts on chicken eggs and mice. Dexamethasone in concentrations observed in plasma of patients favored epithelial–mesenchymal transition, self-renewal potential and cancer progression. Ras/JNK signaling, enhanced expression of TGFβ, vimentin, Notch-1 and SOX-2 and the inhibition of E-cadherin occurred. This was confirmed in patient and xenograft tissue, where dexamethasone induced tumor proliferation, gemcitabine resistance and metastasis. Inhibition of each TGFβ receptor-I, glucocorticoid receptor or JNK signaling partially reversed the dexamethasone-mediated effects, suggesting a complex signaling network. These data reveal that dexamethasone mediates progression by membrane effects and binding to glucocorticoid receptor.

Dexamethasone Inhibits Spheroid Formation of Thyroid Cancer Cells Exposed to Simulated Microgravity

“…DEX supplementation led to a slow downregulation of TGFB1 expression in static cell cultures or in follicular thyroid cancer cells grown for four hours on the RPM ( Figure S2C). This observation could be cell-type specific, as DEX increased TGFB1 expression in prostate cancer and pancreatic ductal carcinoma cells [76,77]. TGF-β signaling is identified as one of the most altered pathways in ovarian tumor spheroids [78] and cell aggregation proved to be induced by TGF-β in ovarian cancer cells [79].…”

Dexamethasone-induced inhibition of miR-132 via methylation promotes TGF-β-driven progression of pancreatic cancer

“…However, for epithelial tumors such as PDA, accumulating evidence indicates that GCs have anti-apoptotic effects and induce cancer progression and therapy resistance ( 5 , 6 ). In 2003, we reported the first in vivo evidence of induction of chemotherapy resistance due to pharmacological doses of DEX in a lung and cervical cancer cell line ( 7 ), and these data have been confirmed by several experimental studies ( 4 - 6 , 8 ). Additionally, clinical studies have indicated an increased likelihood of drug resistance, disease progression and metastasis in patients with glioblastoma, oral squamous cell carcinoma and cancers of the ovary, breast, prostate or lung due to GCs ( 8 - 15 ).…”

“…The present study is based on our recent finding that DEX meditates PDA progression through its actions on the GC receptor, TGF-β and JNK/AP1 ( 4 ) Here, we evaluate the mechanism underlying DEX-induced upregulation of TGF-β. Because a number of studies have suggested that miRNAs are important mediators of GC signaling ( 35 , 36 ), we performed miRNA microarray analysis and identified several significantly DEX-deregulated miRNAs, with miR-132 as the top down-regulated candidate.…”

“…Dexamethasone (DEX), a potent synthetic GC, is often prescribed for lymphoid cancer, and is also a co-treatment for PDA and other types of epithelial tumors. Furthermore, GCs may limit the side effects of chemotherapy and cancer growth, reduce inflammation in pancreatitis, which is often associated with PDA, and inhibit tumor cachexia and pain ( 4 ). However, for epithelial tumors such as PDA, accumulating evidence indicates that GCs have anti-apoptotic effects and induce cancer progression and therapy resistance ( 5 , 6 ).…”

“…Similarly, an increased risk for skin and bladder cancer as well as non-Hodgkin lymphoma has been observed among systemic GC users ( 16 , 17 ). Our latest data based on PDA cells demonstrate that DEX treatment mediates cancer progression and metastasis by inducing the epithelial-mesenchymal transition (EMT), and cancer stem cell (CSC) signaling through the activation of c-Jun N-terminal kinase (JNK)/c-Jun and transforming growth factor-β (TGF-β) pathways ( 4 ).…”