Dexamethasone enhances cell resistance to chemotherapy by increasing adhesion to extracellular matrix in human ovarian cancer cells.

Glucocorticoids (GCs) are widely used as co-medication in the therapy of solid malignant tumors to relieve some of the side effects of chemotherapeutic drugs. However, recent studies have shown that GCs could render cancer cells more resistant to cytotoxic drug-induced apoptosis, but the mechanism is largely unknown. In the present study, we found that the treatment of human ovarian cancer cell lines HO-8910 and SKOV3 with synthetic GCs dexamethasone (Dex) significantly increased their adhesion to extracellular matrix (ECM) and their resistance to apoptosis induced by cytotoxic drugs cisplatin and paclitaxel. Dex also increased the protein levels of adhesion molecules integrins beta1, alpha 4, and alpha 5 in HO-8910 cells. The neutralizing antibody against integrin beta1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that transforming growth factor-beta1 (TGF-beta1) alone not only increased cell adhesion and cell survival of HO-8910 cells in the presence of cisplatin, but also had synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-beta1-neutralizing antibody that could block TGF-beta1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-beta1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-beta receptor type II and enhance the responsiveness of cells to TGF-beta1. In conclusion, our results indicate that increased adhesion to ECM through the enhancement of integrin beta1 signaling and TGF-beta1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells.

Up-regulation of RhoB by glucocorticoids and its effects on the cell proliferation and NF-kappaB transcriptional activity.

Although there is ample evidence that glucocorticoids (GCs) have an antiproliferative effect on many cell types, the molecular mechanism remains elusive. We reported in our previous study that Dex treatment led to cell growth arrest in a human ovarian cancer cell HO-8910. RhoB, as a member of Rho GTPases, have been implicated to be a negative regulator of cell proliferation. In this study, we provided novel evidence that Dex induced the expressions of small GTPase RhoB mRNA and protein, but not RhoA and RhoC mRNA in a dose- and time-dependent fashion via glucocorticoid receptor (GR). Over-expression of RhoB increased while inhibition of RhoB expression by RNA interference reversed Dex-induced growth arrest, indicating that RhoB signaling is involved in Dex-induced proliferation inhibition. We also presented the novel observation that over-expression or activation of RhoB signaling elevated the basal transcriptional activity of the transcription factor NF-kappaB in HO-8910 cells. Furthermore, elevating RhoB signaling enhanced the inhibitory effect of Dex on NF-kappaB activity, while attenuating RhoB signaling almost abrogated Dex suppression of NF-kappaB signaling, indicating that RhoB pathway is involved in the regulation of NF-kappaB activity and is essential for Dex transcriptional repression on NF-kappaB signaling in HO-8910 cells.