Abstract
ObjectivesThis study is to investigate if polymerase I and transcript release factor (PTRF) acts as a modulator in glioblastoma (GBM) chemoresistance.MethodsMultidrug resistant (MDR) GBM cell line U251AR was established by exposing the U251 cell line to imatinib. The 2D-DIGE and MALDI-TOF/TOF-MS were performed on U251 and U251AR cell lines to screen MDR-related proteins. The expression of PTRF was determined by Western blot and quantitative RT-PCR analyses.ResultsWhen compared with the parental U251 cells, expression of 21 proteins was significantly altered in U251AR cells. Among the 21 differentially expressed proteins, the expression of PTRF was up-regulated by 2.14 folds in U251AR cells when compared with that in the parental U251 cells. Knockdown of PTRF in GBM cell lines significantly increased chemosensitivity of cells to various chemical drugs and decreased the expression levels of caveolin1, a major structural component of caveolae. Expression levels of PTRF and caveolin1 were significantly up-regulated in the relapsed GBM patients. The mRNA level of PTRF and caveolin1 showed a positive correlation in the same GBM specimens.ConclusionsOur results indicate that PTRF acts as a modulator in GBM chemoresistance.
Highlights
Glioblastoma (GBM) is one of the most lethal diseases in the central nervous system of adults and the median survival time of GBM patients is 12 months [1]
By using the parental cell line U251, we previously established the imatinib-resistant GBM cell line U251AR, which had a crossresistance to VP-16 and TMZ
The U251AR was cultured in medium with imatinib (122 mg/mL) to maintain the Multidrug resistant (MDR) phenotype
Summary
Glioblastoma (GBM) is one of the most lethal diseases in the central nervous system of adults and the median survival time of GBM patients is 12 months [1]. There are various therapeutic methods for GBM, including surgery, chemotherapy and radiotherapy. The median survival time of patients with GBM was only modestly increased to 15 months [2]. Major limitations of therapies for GBM are tumor recurrence after surgery, tumor infiltration into surrounding tissues, and intrinsic or acquired resistance to chemotherapy and radiotherapy [3]. The DNA-methylating agent temozolomide (TMZ) has been developed for treatment of gliomas [2], several growth factor receptors such as PDGFR and EGFR have been used as therapeutic targets [4,5]. Treatment with the PDGFR/c-KIT/ abl kinase inhibitors dramatically inhibited the viability and anchorage-independent growth of tumor cells [6]. The mechanisms underlying the resistance to RTK inhibitors have not yet been fully elucidated [9]
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