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.
Busse
Antonia
A
Department of Medicine III (Hematology, Oncology, and Transfusion Medicine), Charité, Campus Benjamin Franklin, Berlin, Germany. antonia.busse@charite.de
Kraus
Marianne
M
Na
Il-Kang
IK
Rietz
Anika
A
Scheibenbogen
Carmen
C
Driessen
Christoph
C
Blau
Igor Wolfgang
IW
Thiel
Eckhard
E
Keilholz
Ulrich
U
D000111:Acetylcysteine / Q000031:analogs & derivatives / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D001402:B-Lymphocytes / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001897:Boronic Acids / Q000494:pharmacology; D000069286:Bortezomib; D045744:Cell Line, Tumor; D003546:Cysteine Endopeptidases / Q000378:metabolism; D004354:Drug Screening Assays, Antitumor; D006801:Humans; D007371:Interferon-gamma / Q000494:pharmacology; D008223:Lymphoma / Q000378:metabolism* / Q000473:pathology; D009097:Multienzyme Complexes / Q000378:metabolism; D009101:Multiple Myeloma / Q000378:metabolism* / Q000473:pathology; D011480:Protease Inhibitors / Q000494:pharmacology*; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D021122:Protein Subunits / Q000378:metabolism*; D011719:Pyrazines / Q000494:pharmacology
D001897:Boronic Acids; D009097:Multienzyme Complexes; D011480:Protease Inhibitors; D021122:Protein Subunits; D011719:Pyrazines; C067713:lactacystin; C071313:LMP-2 protein; D000069286:Bortezomib; D007371:Interferon-gamma; D003546:Cysteine Endopeptidases; C077436:LMP7 protein; C098948:PSMB10 protein, human; D046988:Proteasome Endopeptidase Complex; D000111:Acetylcysteine