|
| Status |
Public on Jun 01, 2009 |
| Title |
Compensatory IKKa activation of classical NF-kB signaling during IKKb inhibition |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
|
| Summary |
A subtype of diffuse large B-cell lymphoma (DLBCL), termed activated B-cell-like (ABC) DLBCL, depends on constitutive NF-kB pathway signaling for survival. Small molecule inhibitors of IkB kinase b (IKKb), a key regulator of the NF-kB pathway, kill ABC DLBCL cells and hold promise for the treatment of this lymphoma type. We conducted an RNA interference genetic screen to investigate potential mechanisms of resistance of ABC DLBCL cells to IKKb inhibitors. We screened a library of small hairpin RNAs (shRNAs) targeting 500 protein kinases for shRNAs that would kill an ABC DLBCL cell line in the presence of a small molecule IKKb inhibitor more effectively than in its absence. Two independent shRNAs targeting IKKa synergized with the IKKb inhibitor to kill three different ABC DLBCL cell lines but were not toxic by themselves. Surprisingly, IKKa shRNAs blocked the classical rather than the alternative NF-kB pathway in ABC DLBCL cells, as judged by inhibition of IkBa phosphorylation. IKKa shRNA toxicity was reversed by coexpression of wild type but not kinase inactive forms of IKKa, suggesting that IKKa may directly phosphorylate IkBa under conditions of IKKb inhibition. These results suggest that therapy for ABC DLBCL may be improved by targeting both IKKa and IKKb.
Keywords: compound treatment design
|
| |
|
| Overall design |
Gene expression profiling of OCI-Ly3 cells with or without expressing IKKa shRNA in the presence or absence of 12.5 uM IKKb inhibitor for 2 and 3 days. Four samples were analyzed.
|
| |
|
| Citation(s) |
19104039 |
| |
| Submission date |
Jun 26, 2008 |
| Last update date |
Mar 19, 2012 |
| Contact name |
Louis M. Staudt |
| E-mail(s) |
lstaudt@mail.nih.gov
|
| Phone |
301-402-1892
|
| Organization name |
National Cancer Institute
|
| Department |
Lymphoid Malignancies Branch
|
| Lab |
Louis M Staudt
|
| Street address |
9000 Rockville Pike, Bldg 10, Rm 4N114
|
| City |
Bethesda |
| State/province |
MD |
| ZIP/Postal code |
20892 |
| Country |
USA |
| |
|
| Platforms (1) |
|
| Samples (4)
|
| GSM300730 |
OCI-Ly3 Dox 3 days + Ikk Inhibitor 24 hours - mAdbID:81135 |
| GSM300731 |
OCI-Ly3 Dox 2 days + Ikk Inhibitor 3 hours - mAdbID:81325 |
| GSM300732 |
OCI-Ly3 Dox 2 days - mAdbID:81678 |
|
| Relations |
| BioProject |
PRJNA105739 |
Less...
More...