Targeting PKC: a novel role for beta-catenin in ER stress and apoptotic signaling

• Published in: Blood 2009-02, Vol.113 (7), p.1513-1521
• Main Authors: Raab, Marc S., Breitkreutz, Iris, Tonon, Giovanni, Zhang, Jing, Hayden, Patrick J., Nguyen, Thu, Fruehauf, Johannes H., Lin, Boris K., Chauhan, Dharminder, Hideshima, Teru, Munshi, Nikhil C., Anderson, Kenneth C., Podar, Klaus
• Format: Article
• Language: English
• Subjects: Apoptosis - drug effects; Apoptosis - physiology; beta Catenin - metabolism; Biological and medical sciences; Cell Division - drug effects; Cell Division - physiology; Cell Line, Tumor; Cell physiology; DNA-Binding Proteins - genetics; Endoplasmic Reticulum - drug effects; Endoplasmic Reticulum - metabolism; Fundamental and applied biological sciences. Psychology; Gene Expression Regulation, Neoplastic - drug effects; Humans; Indoles - metabolism; Indoles - pharmacology; JNK Mitogen-Activated Protein Kinases - metabolism; Molecular and cellular biology; Multiple Myeloma - drug therapy; Multiple Myeloma - metabolism; Multiple Myeloma - pathology; Myeloid Neoplasia; Nuclear Proteins - genetics; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - metabolism; RNA, Small Interfering; Signal transduction; Signal Transduction - drug effects; Signal Transduction - physiology; Stress, Physiological - drug effects; Stress, Physiological - physiology; Tumor Protein p73; Tumor Suppressor Proteins - genetics
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-05-157040

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 β-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.