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Series GSE13514 Query DataSets for GSE13514
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
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
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.
Contributor(s) Raab M, Anderson K, Podar K
Citation(s) 19018094
Submission date Nov 07, 2008
Last update date Dec 06, 2018
Contact name Marc Raab
E-mail(s) Marc_Raab@DFCI.HARVARD.EDU,
Organization name Dana Farber Cancer Institute
Street address 44 Binney Street
City Boston
State/province MA
ZIP/Postal code 02115
Country USA
Platforms (1)
GPL571 [HG-U133A_2] Affymetrix Human Genome U133A 2.0 Array
Samples (6)
GSM340848 3_noTx
GSM340849 6_noTx
GSM340850 12_noTx
BioProject PRJNA110119

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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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