TY - JOUR
T1 - Targeting PKC
T2 - a novel role for beta-catenin in ER stress and apoptotic signaling
AU - Raab, Marc S
AU - Breitkreutz, Iris
AU - Tonon, Giovanni
AU - Zhang, Jing
AU - Hayden, Patrick J
AU - Nguyen, Thu
AU - Fruehauf, Johannes H
AU - Lin, Boris K
AU - Chauhan, Dharminder
AU - Hideshima, Teru
AU - Munshi, Nikhil C
AU - Anderson, Kenneth C
AU - Podar, Klaus
PY - 2009/2/12
Y1 - 2009/2/12
N2 - Targeting 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 β-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of β-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 β-catenin activates early endoplasmic reticulum stress signaling via eIF2α, C/EBP-homologous protein (CHOP), and p21, leading to immediate growth inhibition. Furthermore, accumulated β-catenin contributes to enzastaurin-induced cell death. Sequential knockdown of β-catenin, c-Jun, and p73, as well as overexpression of β-catenin or p73 confirmed that accumulated β-catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. Our data reveal a novel role of β-catenin in endoplasmic reticulum (ER) stress-mediated growth inhibition and a new proapoptotic mechanism triggered by ß-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.
AB - Targeting 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 β-catenin in regulating growth and survival of tumor cells. Specifically, inhibition of PKC leads to rapid accumulation of β-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 β-catenin activates early endoplasmic reticulum stress signaling via eIF2α, C/EBP-homologous protein (CHOP), and p21, leading to immediate growth inhibition. Furthermore, accumulated β-catenin contributes to enzastaurin-induced cell death. Sequential knockdown of β-catenin, c-Jun, and p73, as well as overexpression of β-catenin or p73 confirmed that accumulated β-catenin triggers c-Jun-dependent induction of p73, thereby conferring MM cell apoptosis. Our data reveal a novel role of β-catenin in endoplasmic reticulum (ER) stress-mediated growth inhibition and a new proapoptotic mechanism triggered by ß-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.
KW - Apoptosis/drug effects
KW - Cell Division/drug effects
KW - Cell Line, Tumor
KW - DNA-Binding Proteins/genetics
KW - Endoplasmic Reticulum/drug effects
KW - Gene Expression Regulation, Neoplastic/drug effects
KW - Humans
KW - Indoles/metabolism
KW - JNK Mitogen-Activated Protein Kinases/metabolism
KW - Multiple Myeloma/drug therapy
KW - Nuclear Proteins/genetics
KW - Protein Kinase C/antagonists & inhibitors
KW - RNA, Small Interfering
KW - Signal Transduction/drug effects
KW - Stress, Physiological/drug effects
KW - Tumor Protein p73
KW - Tumor Suppressor Proteins/genetics
KW - beta Catenin/metabolism
UR - http://www.scopus.com/inward/record.url?scp=61849179573&partnerID=8YFLogxK
U2 - 10.1182/blood-2008-05-157040
DO - 10.1182/blood-2008-05-157040
M3 - Journal article
C2 - 19018094
SN - 0006-4971
VL - 113
SP - 1513
EP - 1521
JO - Blood
JF - Blood
IS - 7
ER -