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Y Chen, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
Y Wang, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
C Fu, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
F Diao, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
L Song, Department of Medicine,, Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, United States
Z Li, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
R Yang, Department of Pathophysiology, the Second Military Medical University, Shanghai, China
J Lu, Department of Pathophysiology, the Second Military Medical University, Shanghai, China

Yu-Xia Chen, Email: cyx73{at}yahoo.com.cn

Abstract

Glucocorticoids (GCs) are widely used as co-medication in therapy of solid malignant tumors to relieve some of the side effects of chemotherapy 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 integrin β1, 4 and V in HO-8910 cells. The neutralizing antibody against integrin β1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that TGF-β1 alone not only increased cell adhesion and cell survival of HO-8910 cells in the presence of cisplatin, but also has synergistic pro-adhesion and pro-survival effects with Dex. Moreover, TGF-β1 neutralizing antibody that could block TGF-β1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-β1. Finally, we further demonstrated that Dex could up-regulate the expression of TGF-β receptor type II (TβRII) and enhance the responsiveness of cells to TGF-β1. In conclusion, our results indicate that increased adhesion to ECM through enhancing integrin β1 signaling and TGF-β1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells.