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Updated: Jun 27, 2026

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death
09:18

Identification of Intracellular Signaling Events Induced in Viable Cells by Interaction with Neighboring Cells Undergoing Apoptotic Cell Death

Published on: December 27, 2016

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

Marc S Raab1, Iris Breitkreutz, Giovanni Tonon

  • 1LeBow 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

Blood
|November 20, 2008
PubMed

Insights

Enzastaurin inhibits protein kinase C (PKC) in multiple myeloma, causing beta-catenin accumulation. This triggers endoplasmic reticulum stress and apoptosis, revealing p73 as a therapeutic target.

Area of Science:

  • Molecular Biology
  • Cancer Research
  • Pharmacology

Background:

  • Protein kinase C (PKC) inhibitors, like enzastaurin, show preclinical anti-cancer activity.
  • The precise mechanisms of enzastaurin in multiple myeloma (MM) require further elucidation.
  • Beta-catenin's role in cancer cell growth and survival is complex and context-dependent.

Purpose of the Study:

  • To investigate the mechanism of action of enzastaurin in multiple myeloma cells.
  • To identify the role of beta-catenin in mediating enzastaurin's effects.
  • To explore novel therapeutic targets in multiple myeloma based on enzastaurin's action.

Main Methods:

  • Treatment of multiple myeloma cells with enzastaurin.
  • Analysis of beta-catenin accumulation and phosphorylation.
  • Microarray analysis and siRNA-mediated gene silencing to assess signaling pathways.
  • Investigation of downstream targets including eIF2alpha, CHOP, p21, c-Jun, and p73.

Main Results:

  • Enzastaurin inhibits PKC, leading to beta-catenin accumulation by preventing its degradation.
  • Accumulated beta-catenin induces endoplasmic reticulum (ER) stress via eIF2alpha, CHOP, and p21, causing growth inhibition.
  • Beta-catenin accumulation triggers c-Jun-dependent induction of p73, promoting apoptosis in MM cells.
  • p73 is identified as a key mediator of enzastaurin-induced apoptosis.

Conclusions:

  • Beta-catenin plays a novel role in ER stress-mediated growth inhibition and apoptosis induction upon PKC inhibition.
  • Enzastaurin induces MM cell death through a novel beta-catenin/c-Jun/p73 apoptotic pathway.
  • p73 represents a potential novel therapeutic target for multiple myeloma treatment.

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