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Src Family Kinases as Proteasome Regulators and Therapeutic Targets for Treatment of Diffuse Large B‐cell Lymphoma
Author(s) -
Cann Marissa,
Priestman Melanie,
Wang Qunzhao,
Lawrence David
Publication year - 2016
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.30.1_supplement.633.4
Subject(s) - dasatinib , diffuse large b cell lymphoma , proteasome , cancer research , proteasome inhibitor , src family kinase , kinase , germinal center , signal transduction , lymphoma , biology , proto oncogene tyrosine protein kinase src , b cell , medicine , tyrosine kinase , microbiology and biotechnology , immunology , antibody
Diffuse large B‐cell lymphoma (DLBCL) patients can be categorized into two clinically relevant subtypes: activated B‐cell (ABC) and germinal center B‐cell (GCB). Since patients with ABC DLBCL tend to have a much worse prognosis than their GCB DLBCL counterparts, there is great interest in identifying effective drug targets for the treatment of this subtype. Chronic, overactive signaling through the B‐cell receptor and the anti‐apoptotic NF‐κB pathway are hallmarks of the ABC, but not the GCB DLBCL subtype. Interestingly, the Src family kinases (SFKs) are known to play important roles in both of these signaling pathways. Additionally, since the proteasome is also important for maintaining NF‐κB activity and is a target of interest for the treatment of ABC DLBCL, we hypothesized that the SFKs play a role in the regulation of the proteasome. In this study we explored this role and its potential as a therapeutic target for the treatment of DLBCL. We treated a panel of ABC and GCB DLBCL cell lines with the SFK inhibitor dasatinib and found that the ABC DLBCL cell lines are significantly more sensitive to dasatinib than the GCB DLBCL cell lines. To determine if this sensitivity to dasatinib was linked to regulation of the proteasome by SFKs, a set of novel peptide sensors were used to monitor the proteasome's chymotrypsin‐like, trypsin‐like, and caspase‐like activities. Using these sensors, we demonstrate that treatment of DLBCL cell lines with the SFK inhibitor dasatinib results in a marked decrease in chymotrypsin‐like proteasome activity for the ABC DLBCL cell lines, whereas nominal changes are observed in the GCB DLBCL cell lines. Biochemical analyses demonstrate that while there is minimal change in expression of the β5 proteasome subunit, which is responsible for the proteasome's chymotrypsin‐like activity, dasatinib treatment induces a decrease in expression of the proteasome 19S regulatory particle in isolated proteasomes. However, 19S expression remains unchanged in whole lysates, indicating that the SFKs might regulate the proteasome through a chaperone protein that helps assemble or stabilize proteasome complexes. Taken together, our data suggest that inhibition of the SFKs with dasatinib affects proteasome assembly in addition to B‐cell receptor signaling, thus making ABC DLBCL cell lines particularly sensitive to dasatinib treatment. Support or Funding Information This project was supported by the National Center for Advancing Translational Sciences, National Institutes of Health, through Grant Award Number TL1TR001110. The project is currently supported by the National Cancer Institute of the National Institutes of Health under Award Number F31CA196153. The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.