Inhibition of proliferation and survival of diffuse large B-cell lymphoma cells by a small-molecule inhibitor of the ubiquitin-conjugating enzyme Ubc13-Uev1A.
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Abstract | Diffuse large B-cell lymphoma (DLBCL), the most common type of non-Hodgkin lymphoma, remains a partially curable disease. Genetic alterations affecting components of NF-κB signaling pathways occur frequently in DLBCL. Almost all activated B cell-like (ABC) DLBCL, which is the least curable group among the 3 major subtypes of this malignancy, and a substantial fraction of germinal center B cell-like (GCB) DLBCL exhibit constitutive NF-κB pathway activity. It has been demonstrated that ABC-DLBCL cells require such activity for proliferation and survival. Therefore, inhibition of NF-κB activation in DLBCL may provide an efficient and targeted therapy. In screening for small-molecule compounds that may inhibit NF-κB activation in DLBCL cells, we identified a compound, NSC697923, which inhibits the activity of the ubiquitin-conjugating (E2) enzyme Ubc13-Uev1A. NSC697923 impedes the formation of the Ubc13 and ubiquitin thioester conjugate and suppresses constitutive NF-κB activity in ABC-DLBCL cells. Importantly, NSC697923 inhibits the proliferation and survival of ABC-DLBCL cells and GCB-DLBCL cells, suggesting the Ubc13-Uev1A may be crucial for DLBCL growth. Consistently, knockdown of Ubc13 expression also inhibited DLBCL cell survival. The results of the present study indicate that Ubc13-Uev1A may represent a potential therapeutic target in DLBCL. In addition, compound NSC697923 may be exploited for the development of DLBCL therapeutic agents. |
Year of Publication | 2012
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Journal | Blood
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Volume | 120
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Issue | 8
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Pages | 1668-77
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Date Published | 2012 Aug 23
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ISSN | 1528-0020
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DOI | 10.1182/blood-2012-02-406074
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PubMed ID | 22791293
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PubMed Central ID | PMC3429308
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Grant list | R37 AI049660 / AI / NIAID NIH HHS / United States
CA130805-02S2 / CA / NCI NIH HHS / United States
U19-AI56390 / AI / NIAID NIH HHS / United States
U19 AI056390 / AI / NIAID NIH HHS / United States
R01 CA127530 / CA / NCI NIH HHS / United States
P50 CA130805 / CA / NCI NIH HHS / United States
P01 AI078907 / AI / NIAID NIH HHS / United States
1P50CA130805 / CA / NCI NIH HHS / United States
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