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| Status |
Public on Nov 11, 2008 |
| Title |
Targeting PKC: A Novel Role for beta-catenin in ER stress and Apoptotic Signaling |
| Organism |
Homo sapiens |
| Experiment type |
Expression profiling by array
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| Summary |
Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising pre-clinical activity in a wide range of tumor cells. In this study, we further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of b-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of b-catenin by preventing the phosphorylation required for its proteasomal degradation. Microarray analysis and siRNA-mediated gene silencing in MM cells revealed that accumulated b-catenin activates early ER stress signaling via eIF2a, CHOP and p21, leading to immediate growth inhibition. Furthermore, accumulated b-catenin contributes to enzastaurin-induced cell death. Both sequential knock-down of b-catenin, c-Jun, and p73, as well as overexpression of b-catenin or p73 confirmed that accumulated b-catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. In summary, our data reveal a novel role of b-catenin in ER stress-mediated growth inhibition, and a new pro-apoptotic mechanism triggered by b-catenin upon inhibition of PKC isoforms. Moreover, we identify p73 as a potential novel therapeutic target in MM. Based on these and previous data, enzastaurin is currently under clinical investigation in a variety of hematologic malignancies including MM.
Keywords: time course
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| Overall design |
MM.1S myeloma cell lines were treated with enzastaurin for 3, 6 or 12 hours. Controls are represented by untreated cells, at the same time points.
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| Contributor(s) |
Raab M, Anderson K, Podar K |
| Citation(s) |
19018094 |
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| Submission date |
Nov 07, 2008 |
| Last update date |
Dec 06, 2018 |
| Contact name |
Marc Raab |
| E-mail(s) |
[email protected], [email protected]
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| Organization name |
Dana Farber Cancer Institute
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| Street address |
44 Binney Street
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| City |
Boston |
| State/province |
MA |
| ZIP/Postal code |
02115 |
| Country |
USA |
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| Platforms (1) |
| GPL571 |
[HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array |
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| Samples (6)
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| Relations |
| BioProject |
PRJNA110119 |
| Supplementary file |
Size |
Download |
File type/resource |
| GSE13514_RAW.tar |
11.8 Mb |
(http)(custom) |
TAR (of CEL) |
| Processed data included within Sample table |
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