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Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits

Item Type:Article
Title:Sensitivity of tumor cells to proteasome inhibitors is associated with expression levels and composition of proteasome subunits
Creators Name:Busse, A. and Kraus, M. and Na, I.K. and Rietz, A. and Scheibenbogen, C. and Driessen, C. and Blau, I.W. and Thiel, E. and Keilholz, U.
Abstract:Background: Sensitivity of tumor cells to induction of apoptosis by proteasome inhibitors varies greatly. This study was undertaken to investigate the sensitivity of neoplastic B cells and solid tumor cells to proteasome inhibition with respect to constitutive expression levels of proteasome subunits. Methods: Twelve neoplastic B-cell lines and 12 solid tumor cell lines were assessed for their expression levels of proteasome subunits by using quantitative reverse transcriptase-polymerase chain reaction analysis and were assessed for their sensitivity to the proteasome inhibitors PS-341 and lactacystin by using a flow cytometry assay that detected activated caspases. Results: The neoplastic B-cell lines were categorized into 3 groups representing refractory cell lines, cell lines with moderate sensitivity, and cell lines with high sensitivity. Correlating expression levels of proteasome subunits with sensitivity to proteasome inhibition indicated that refractory B cells exhibited lower expression levels of the standard subunit beta2 and of the immunoproteasome subunit LMP2 compared with sensitive B cell lines. Compared with neoplastic B cells solid tumor cells were less sensitive. They expressed the immunoproteasome subunits LMP2, LMP7 and MECL-1 and the standard subunit beta2 clearly below the median of the expression level of the sensitive B cell lines. IFN-gamma pretreatment enhanced sensitivity to PS-341 in 50% of the tumor cell lines, potentially related to the induction of immunoproteasomes. Conclusions: The results of this study indicated that sensitivity to proteasome inhibition is correlated with expression levels of proteasome subunits, which determine the enzymatic activity of the proteasome. Combining PS-341 with IFN-gamma may enhance its clinical efficacy.
Keywords:Apoptosis Induction, Proteasome Inhibition, PS-341, Solid Tumors, B-Cell Neoplasia, Interferon {gamma}
Page Range:659-670
Date:1 February 2008
Official Publication:https://doi.org/10.1002/cncr.23224
PubMed:View item in PubMed

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