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

Marc S Raab, Iris Breitkreutz, Giovanni Tonon, Jing Zhang, Patrick J Hayden, Thu Nguyen, Johannes H Fruehauf, Boris K Lin, Dharminder Chauhan, Teru Hideshima, Nikhil C Munshi, Kenneth C Anderson, Klaus Podar

Research output: Journal article (peer-reviewed)Journal article

64 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)1513-1521
Number of pages9
Issue number7
Publication statusPublished - 12 Feb 2009
Externally publishedYes


  • Apoptosis/drug effects
  • Cell Division/drug effects
  • Cell Line, Tumor
  • DNA-Binding Proteins/genetics
  • Endoplasmic Reticulum/drug effects
  • Gene Expression Regulation, Neoplastic/drug effects
  • Humans
  • Indoles/metabolism
  • JNK Mitogen-Activated Protein Kinases/metabolism
  • Multiple Myeloma/drug therapy
  • Nuclear Proteins/genetics
  • Protein Kinase C/antagonists & inhibitors
  • RNA, Small Interfering
  • Signal Transduction/drug effects
  • Stress, Physiological/drug effects
  • Tumor Protein p73
  • Tumor Suppressor Proteins/genetics
  • beta Catenin/metabolism

ASJC Scopus subject areas

  • Hematology
  • Biochemistry
  • Cell Biology
  • Immunology


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