Novel targets for endoplasmic reticulum stress-induced apoptosis in B-CLL

Blood. 2010 Oct 14;116(15):2713-23. doi: 10.1182/blood-2010-03-275628. Epub 2010 Jul 13.

Abstract

A better understanding of apoptotic signaling in B-chronic lymphocytic leukemia (B-CLL) cells may help to define new therapeutic strategies. This study investigated endoplasmic reticulum (ER) stress signaling in spontaneous apoptosis of B-CLL cells and whether manipulating ER stress increases their apoptosis. Results show that a novel ER stress-triggered caspase cascade, initiated by caspase-4 and involving caspase-8 and -3, plays an important role in spontaneous B-CLL cell apoptosis. ER stress-induced apoptosis in B-CLL cells also involves CHOP/GADD153 up-regulation, increased JNK1/2 phosphorylation, and caspase-8-mediated cleavage of Bap31 to Bap20, known to propagate apoptotic signals from ER to mitochondria. In ex vivo B-CLL cells, some apoptotic events associated with mitochondrial pathway also occur, including mitochondrial cytochrome c release and caspase-9 processing. However, pharmacologic inhibition studies show that caspase-9 plays a minor role in B-CLL cell apoptosis. ER stress also triggers survival signals in B-CLL cells by increasing BiP/GRP78 expression. Manipulating ER signaling by siRNA down-regulation of BiP/GRP78 or treating B-CLL cells with 2 well-known ER stress-inducers, tunicamycin and thapsigargin, increases their apoptosis. Overall, our findings show that ER triggers an essential pathway for B-CLL cell apoptosis and suggest that genetic and pharmacologic manipulation of ER signaling could represent an important therapeutic strategy.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis / physiology*
  • Caspases / metabolism
  • Down-Regulation
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism*
  • Endoplasmic Reticulum Chaperone BiP
  • Gene Rearrangement, B-Lymphocyte
  • Heat-Shock Proteins / antagonists & inhibitors
  • Heat-Shock Proteins / genetics
  • Humans
  • In Vitro Techniques
  • Leukemia, Lymphocytic, Chronic, B-Cell / genetics
  • Leukemia, Lymphocytic, Chronic, B-Cell / metabolism*
  • Leukemia, Lymphocytic, Chronic, B-Cell / pathology*
  • Leukemia, Lymphocytic, Chronic, B-Cell / therapy
  • Membrane Proteins / metabolism
  • Models, Biological
  • RNA, Small Interfering / genetics
  • Signal Transduction / drug effects
  • Stress, Physiological
  • Thapsigargin / pharmacology
  • Tunicamycin / pharmacology

Substances

  • BCAP31 protein, human
  • Endoplasmic Reticulum Chaperone BiP
  • HSPA5 protein, human
  • Heat-Shock Proteins
  • Membrane Proteins
  • RNA, Small Interfering
  • Tunicamycin
  • Thapsigargin
  • Caspases