Upregulation of drug transporter expression by osteopontin in prostate cancer cellss
Journal
Molecular Pharmacology
Journal Volume
83
Journal Issue
5
Pages
968-977
Date Issued
2013
Author(s)
Abstract
Multidrug resistance is a major cause of 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 the tumor microenvironment. Osteopontin (OPN), an extracellular matrix protein, has a functional arginine-glycine-aspartic acid (RGD) domain for binding to integrin. Here we found OPN expression to be upregulated by hypoxic condition in PC-3 prostate tumor cells. OPN increased the mRNA and protein expression of pglycoprotein (P-gp), a subfamily of ATP-binding cassette transporter in a concentration- and time-dependent manner. The increase in P-gp transporter by OPN was mediated by binding to avb3 integrin. Daunomycin (DUN), a chemotherapeutic agent with autofluorescence, was used to evaluate the pump activity, and OPN increased the drug pumping-out activity. OPN inhibited DUN-induced cell death, which was antagonized by avb3 monoclonal antibody. Long-term treatment with DUN further enhanced the expression of OPN. Knockdown of endogenous OPN potentiated the DUN-induced apoptosis of PC-3 cells. Furthermore, knockdown of OPN enhanced cell death caused by other drugs, including paclitaxel, doxorubicin, actinomycin- D, and rapamycin, which are also P-gp substrates. The animal studies also showed that OPN knockdown enhanced the cytotoxic action of DUN. These results indicate that OPN is a potential therapeutic target for cancer therapy to reduce drug resistance in sensitive tumors. ? 2013 by The American Society for Pharmacology and Experimental Therapeutics.
SDGs
Other Subjects
dactinomycin; daunorubicin; doxorubicin; messenger RNA; monoclonal antibody; multidrug resistance protein; osteopontin; paclitaxel; rapamycin; vitronectin receptor; animal experiment; animal tissue; apoptosis; article; autofluorescence; cancer cell; cancer chemotherapy; cancer resistance; cell death; cell viability; chronic drug administration; controlled study; cytotoxicity; dose time effect relation; drug targeting; gene expression; gene silencing; homeostasis; human; human cell; hypoxia; male; mouse; nonhuman; priority journal; prostate cancer; protein degradation; protein expression; protein function; upregulation; Animals; Apoptosis; Cell Death; Cell Hypoxia; Cell Line, Tumor; Daunorubicin; Drug Resistance, Neoplasm; Humans; Integrin alphaVbeta3; Male; Mice; Mice, Inbred NOD; Mice, SCID; Osteopontin; P-Glycoprotein; Prostatic Neoplasms; Up-Regulation; Xenograft Model Antitumor Assays
Type
journal article