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lüll Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling Raab MS; Breitkreutz I; Tonon G; Zhang J; Hayden PJ; Nguyen T; Fruehauf JH; Lin BK; Chauhan D; Hideshima T; Munshi NC; Anderson KC; Podar KBlood 2009[Feb]; 113 (7): 1513-21Targeting protein kinase C (PKC) isoforms by the small molecule inhibitor enzastaurin has shown promising preclinical activity in a wide range of tumor cells. We further delineated its mechanism of action in multiple myeloma (MM) cells and found a novel role of beta-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of beta-catenin by preventing the phosphorylation required for its proteasomal degradation. Microarray analysis and small-interfering RNA (siRNA)-mediated gene silencing in MM cells revealed that accumulated beta-catenin activates early endoplasmic reticulum stress signaling via eIF2alpha, C/EBP-homologous protein (CHOP), and p21, leading to immediate growth inhibition. Furthermore, accumulated beta-catenin contributes to enzastaurin-induced cell death. Sequential knockdown of beta-catenin, c-Jun, and p73, as well as overexpression of beta-catenin or p73 confirmed that accumulated beta-catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. Our data reveal a novel role of beta-catenin in endoplasmic reticulum (ER) stress-mediated growth inhibition and a new proapoptotic mechanism triggered by beta-catenin on 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.|Apoptosis/drug effects/*physiology[MESH]|Cell Division/drug effects/physiology[MESH]|Cell Line, Tumor[MESH]|DNA-Binding Proteins/genetics[MESH]|Endoplasmic Reticulum/drug effects/*metabolism[MESH]|Gene Expression Regulation, Neoplastic/drug effects[MESH]|Humans[MESH]|Indoles/metabolism/pharmacology[MESH]|JNK Mitogen-Activated Protein Kinases/metabolism[MESH]|Multiple Myeloma/drug therapy/*metabolism/pathology[MESH]|Nuclear Proteins/genetics[MESH]|Protein Kinase C/antagonists & inhibitors/*metabolism[MESH]|RNA, Small Interfering[MESH]|Signal Transduction/drug effects/physiology[MESH]|Stress, Physiological/drug effects/physiology[MESH]|Tumor Protein p73[MESH]|Tumor Suppressor Proteins/genetics[MESH]|beta Catenin/*metabolism[MESH] |