Combined RNA-expression and 2D-PAGE-screening identifies comprehensive interaction networks affected after bortezomib or enzastaurin exposure of mantle cell lymphoma.
Despite recent advances in treatment, mantle cell lymphoma (MCL) still represents a disease with dismal prognosis due to its progressive clinical course, high rate of therapy refractory cases and frequent relapses. During recent years, the proteasome inhibitor bortezomib and enzastaurin, an inhibitor of protein kinase c have been explored in MCL. In relapsed disease enzastaurin achieved disease stabilization in a subset of patients. Bortezomib in relapsed and refractory MCL achieves response rates of 30-40%. To identify signal pathways and manifold interactions regulating cellular response to molecular targeted approaches several high throughput screening methods were applied. A combined network analysis of the identified target molecules based on both RNA array expression data and a survey of cellular protein levels resulted in a unified interaction network more comprehensive (bortezomib: 394 and enzastaurin: 174 molecules) than the networks of the individual screening techniques (329/44 and 117/36 molecules respectively). Interestingly, although none of the target molecules were matched in both RNA-expression and protein level analysis they were mapped nonetheless to common pathways. Additionally, the ranking of identified pathways allowed an improved characterization of the observed induction of cell apoptosis.
Weinkauf
Marc
M
Clinical Cooperative Group Leukemia, Campus Grosshadern Medical Clinic III and Helmholtz Center Munich, Marchioninistr. 25, 81377 Munich, Germany.
Hutter
Grit
G
Zimmermann
Yvonne
Y
Hartmann
Elena
E
Rosenwald
Andreas
A
Dreyling
Martin
M
D017209:Apoptosis / Q000187:drug effects*; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000235:genetics; D004357:Drug Synergism; D015180:Electrophoresis, Gel, Two-Dimensional / Q000379:methods*; D020869:Gene Expression Profiling / Q000379:methods*; D057166:High-Throughput Screening Assays; D006801:Humans; D007211:Indoles / Q000494:pharmacology*; D020522:Lymphoma, Mantle-Cell / Q000235:genetics / Q000473:pathology*; D011379:Prognosis; D011480:Protease Inhibitors / Q000494:pharmacology; D011493:Protein Kinase C / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines / Q000494:pharmacology*; D012008:Recurrence
D001897:Boronic Acids; D007211:Indoles; D011480:Protease Inhibitors; D019253:Proto-Oncogene Proteins c-bcl-2; D011719:Pyrazines; D000069286:Bortezomib; D011493:Protein Kinase C; C504878:enzastaurin