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

被引：56

作者：

Chen, Yu-Xia ^{[1
]}

Wang, Yan ^{[1
]}

Fu, Chen-Chun ^{[1
]}

Diao, Fei ^{[1
]}

Song, Liang-Nian ^{[2
]}

Li, Zong-Bin ^{[1
]}

Yang, Rui ^{[1
]}

Lu, Jian ^{[1
]}

机构：

[1] Second Mil Med Univ, Dept Pathophysiol, Shanghai 200433, Peoples R China

[2] Columbia Univ, Med Ctr, Dept Med, Herbert Irving Comprehens Canc Ctr, New York, NY 10032 USA

来源：

基金：

中国国家自然科学基金;

关键词：

GROWTH-FACTOR-BETA; MAMMARY EPITHELIAL-CELLS; SOLID TUMORS; MOLECULAR-MECHANISMS; MICROARRAY ANALYSIS; INDUCED APOPTOSIS; GENE-EXPRESSION; GLUCOCORTICOIDS; SURVIVAL; FIBRONECTIN;

D O I：

10.1677/ERC-08-0296

中图分类号：

R73 [肿瘤学];

学科分类号：

100214 ;

摘要：

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 beta 1, alpha 4, and alpha 5 in HO-8910 cells. The neutralizing antibody against integrin b1 prevented Dex-induced adhesion and significantly abrogated the protective effect of Dex toward cytotoxic agents. We further found that transforming growth factor-beta 1 (TGF-beta 1) 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-beta 1-neutralizing antibody that could block TGF-beta 1-induced cell adhesion and apoptosis resistance markedly abrogated the synergistic pro-adhesion and pro-survival effects of Dex and TGF-beta 1. 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-beta 1. In conclusion, our results indicate that increased adhesion to ECM through the enhancement of integrin beta 1 signaling and TGF-beta 1 signaling plays an important role in chemoresistance induced by GCs in ovarian cancer cells. Endocrine-Related Cancer (2010) 17 39-50

引用

页码：39 / 50

页数：12

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