RT Journal Article
SR Electronic
T1 Upregulation of Drug Transporter Expression by Osteopontin in Prostate Cancer Cells
JF Molecular Pharmacology
JO Mol Pharmacol
FD American Society for Pharmacology and Experimental Therapeutics
SP mol.112.082339
DO 10.1124/mol.112.082339
A1 I-Shan Hsieh
A1 Wei-Hsun Huang
A1 Houng-Chi Liou
A1 Woei-Jer Chuang
A1 Rong-Sen Yang
A1 Wen-Mei Fu
YR 2013
UL http://molpharm.aspetjournals.org/content/early/2013/02/22/mol.112.082339.abstract
AB Multidrug resistance (MDR) is a major cause leading to chemotherapy failure. Recent studies indicate that drug resistance can be rapidly induced by some soluble factors, such as cytokines, chemokines, growth factors and cell adhesion factors in tumor microenvironment. Osteopontin, an extracellular matrix protein, has a functional RGD domain for binding to integrin. Here we found that osteopontin expression was up-regulated by hypoxic condition in PC-3 prostate tumor cells. Osteopontin increased the mRNA and protein expression of p-glycoprotein, a subfamily of ATP-binding cassette transporter, in a concentration- and time-dependent manner. The increase of p-glycoprotein transporter by osteopontin was mediated by binding to αvβ3 integrin. Daunomycin, a chemotherapeutic agent with autofluorescence, was used to evaluate the pump activity and osteopontin was found to increase the drug pumping-out activity. Osteopontin inhibited daunomycin-induced cell death, which was antagonized by αvβ3 monoclonal antibody. Long-term treatment with daunomycin further enhanced the expression of osteopontin. Knockdown of endogenous osteopontin potentiated the daunomycin-induced apoptosis of PC-3 cells. Furthermore, knockdown of osteopontin also enhanced the cell death caused by other drugs, including paclitaxel, doxorubicin, actinomycin-D and rapamycin, which are also the p-glycoprotein substrate. The animal studies also showed that osteopontin knockdown enhanced the cytotoxic action of daunomycin. These results indicate that osteopontin is a potential therapeutic target for cancer therapy to reduce the drug resistance in sensitive tumors.