Abstract
BackgroundMultidrug resistance-related protein 1 (MRP1/ABCC1) and multidrug resistance protein 1 (MDR1/P-glycoprotein/ABCB1) are both membrane-bound drug transporters. In contrast to MDR1, MRP1 also transports glutathione (GSH) and drugs conjugated to GSH. Due to its extraordinary transport properties, MRP1/ABCC1 contributes to several physiological functions and pathophysiological incidents. We previously found that nuclear translocation of MRP1 contributes to multidrug-resistance (MDR) of mucoepidermoid carcinoma (MEC). The present study investigated how MRP1 contributes to MDR in the nuclei of MEC cells.MethodsWestern blot and RT-PCR was carried out to investigate the change of multidrug-resistance protein 1 (MDR1) in MC3/5FU cells after MRP1 was downregulated through RNA interference (RNAi). Immunohistochemistry (IHC) staining of 127 cases of MEC tissues was scored with the expression index (EI). The EI of MDR1 and MRP1 (or nuclear MRP1) was analyzed with Spearman's rank correlation analysis. Using multiple tumor tissue assays, the location of MRP1 in other tissues was checked by HIC. Luciferase reporter assays of MDR1 promoter was carried out to check the connection between MRP1 and MDR1 promoter.ResultsMRP1 downregulation led to a decreased MDR1 expression in MC3/5FU cells which was caused by decreased activity of MDR1 promoter. IHC study of 127 cases of MEC tissues demonstrated a strong positive correlation between nuclear MRP1 expression and MDR1 expression. Furthermore, IHC study of multiple tumor tissue array sections showed that although nuclear MRP1 widely existed in MEC tissues, it was not found in normal tissues or other tumor tissues.ConclusionsOur findings indicate that nuclear MRP1 contributes to MDR mainly through regulating MDR1 expression in MEC. And the unique location of MRP1 made it an available target in identifying MEC from other tumors.
Highlights
Mucoepidermoid carcinoma (MEC) is the most common primary malignant salivary gland tumor in occidental and Chinese population [1,2,3]
We found nuclear MRP1 in mucoepidermoid carcinoma (MEC) cells for the first time and proved that nuclear translocation of MRP1 was one of the reasons leading to multidrug-resistance of MC3/5FU cells [13]
To explore why the downregulation of MRP1 reversed the resistance to taxol which is not the substrate of MRP1 [13] but the substrate of multidrug-resistance protein 1 (MDR1) [9], we investigated MDR1 expression in MC3/5FU cells when MRP1 was downregulated through shorthairpin RNAs in this study
Summary
Mucoepidermoid carcinoma (MEC) is the most common primary malignant salivary gland tumor in occidental and Chinese population [1,2,3]. It comprises about 10% of all salivary gland neoplasms and about 35% of malignant lesions [4]. MEC comprises about 16% of all salivary gland neoplasms and about 51% of malignant lesions [5]. Multidrug resistance-related protein 1 (MRP1/ABCC1) and multidrug resistance protein 1 (MDR1/Pglycoprotein/ABCB1) are both membrane-bound drug transporters. We previously found that nuclear translocation of MRP1 contributes to multidrug-resistance (MDR) of mucoepidermoid carcinoma (MEC). The present study investigated how MRP1 contributes to MDR in the nuclei of MEC cells
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