FK506 Binding Protein Mediates Glioma Cell Growth and Sensitivity to Rapamycin Treatment by Regulating NF-κB Signaling Pathway

Abstract

FK506 binding protein 5 (FKBP5) belongs to a family of immunophilins named for their ability to bind immunosuppressive drugs, also known as peptidyl-prolyl cis-trans isomerases, and also with chaperones to help protein folding. Using glioma cDNA microarray analysis, we found that FKBP5 was overexpressed in glioma tumors. This finding was further validated by real-time reverse transcription-polymerase chain reaction and Western blot analysis. The roles of FKBP5 in glioma cells were then examined. We found that cell growth was suppressed after FKBP5 expression was inhibited by short interfering RNA transfection and enhanced by FKBP5 overexpression. Electrophoretic mobility shift assay showed that nuclear factor-kappa B (NF-kappaB) and DNA binding was enhanced by FKBP5 overexpression. The expression level of I-kappa B alpha and phosphorylated NF-kappaB was regulated by the expression of FKBP5. These data suggest that FKBP5 is involved in NF-kappaB pathway activation in glioma cells. In addition, FKBP5 overexpression in rapamycin-sensitive U87 cells blocked the cells' response to rapamycin treatment, whereas rapamycin-resistant glioma cells, both PTEN-positive and -negative, were synergistically sensitive to rapamycin after FKBP5 was knocked down, suggesting that the FKBP5 regulates glioma cell response to rapamycin treatment. In conclusion, our study demonstrates that FKBP5 plays an important role in glioma growth and chemoresistance through regulating signal transduction of the NF-kappaB pathway.

Comprehensive characterization of glioblastoma tumor tissues for biomarker identification using mass spectrometry-based label-free quantitative proteomics

“…These proteins are highly specific to GBM irrespective of their location in brain, thus providing important insights into the disease pathology as has been demonstrated by the validated proteins and their involvement in various events of tumorigenesis. Our analysis also provided several other upregulated proteins, like SERPH, PDIA1, CERU, TENA, VTNC, APOE, LEG1, HRG, and FKBP5, that are known to be involved in tumor progression, aggressiveness, and invasion in GBM (3,17,18,28,30,32,39,45,47). In addition to known GBM-associated proteins, novel potential biomarkers identified in this study include CLIC4, NP1L1, IGKC, TAGL2, and YES (Supplementary Table S1).…”

Coupling of Conformational Transitions in the N-terminal Domain of the 51-kDa FK506-binding Protein (FKBP51) Near Its Site of Interaction with the Steroid Receptor Proteins

“…In hindsight, an early indication of the functional significance for FKBP51 and FKBP52 of the interface between the ␤ 4 -␤ 5 loop and the underlying ␤ 2 and ␤ 3a strands was the widespread use of a F67D,D68V double mutant as a presumed indicator for the participation of the peptidyl prolyl isomerase activity for these proteins in their biological functions, in particular for steroid receptor activity (15,(35)(36)(37)(38). More recently, in the context of their analysis of the effects of the L119P and P119L variants of FKBP51 and FKBP52 in the transcriptional activity of the steroid hormone receptor discussed above, Smith and colleagues (16) compared the F67D,D68V double mutant to other mutations that lay within the catalytic cleft to conclude that the steroid receptor activity does not depend upon prolyl isomerization catalysis.…”

Large FK506-Binding Proteins Shape the Pharmacology of Rapamycin

“…Re- cently, FKBP38 has been proposed as a player in mTOR inhibition, but this effect was largely rapamycin independent and might be indirect (14). The rapamycin sensitivity of glioma cell lines was shown to be affected by FKBP51 expression levels, but this was attributed to the direct role of FKBP51 in NF-B signaling, which is inhibited by FKBP51 ligands (46). The rapamycin levels used in the present work are very low and unlikely to saturate FKBPbinding sites in cells.…”