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

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.