Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling.
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 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.
Raab
Marc S
MS
LeBow Institute for Myeloma Therapeutics and Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA 02115, USA. marc_raab@dfci.harvard.edu
Breitkreutz
Iris
I
Tonon
Giovanni
G
Zhang
Jing
J
Hayden
Patrick J
PJ
Nguyen
Thu
T
Fruehauf
Johannes H
JH
Lin
Boris K
BK
Chauhan
Dharminder
D
Hideshima
Teru
T
Munshi
Nikhil C
NC
Anderson
Kenneth C
KC
Podar
Klaus
K
D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002455:Cell Division / Q000187:drug effects / Q000502:physiology; D045744:Cell Line, Tumor; D004268:DNA-Binding Proteins / Q000235:genetics; D004721:Endoplasmic Reticulum / Q000187:drug effects / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007211:Indoles / Q000378:metabolism / Q000494:pharmacology; D048031:JNK Mitogen-Activated Protein Kinases / Q000378:metabolism; D009101:Multiple Myeloma / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D013312:Stress, Physiological / Q000187:drug effects / Q000502:physiology; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins / Q000235:genetics; D051176:beta Catenin / Q000378:metabolism*
C495270:CTNNB1 protein, human; D004268:DNA-Binding Proteins; D007211:Indoles; D009687:Nuclear Proteins; D034741:RNA, Small Interfering; C000606460:TP73 protein, human; D000072160:Tumor Protein p73; D025521:Tumor Suppressor Proteins; D051176:beta Catenin; D011493:Protein Kinase C; D048031:JNK Mitogen-Activated Protein Kinases; C504878:enzastaurin