Apoptosis

, Volume 11, Issue 7, pp 1175–1193

The TRAIL apoptotic pathway mediates proteasome inhibitor induced apoptosis in primary chronic lymphocytic leukemia cells

  • Albert F. Kabore
  • Jinmie Sun
  • Xiaojie Hu
  • Kristin McCrea
  • James B. Johnston
  • Spencer B. Gibson
Reports

DOI: 10.1007/s10495-006-8048-9

Cite this article as:
Kabore, A.F., Sun, J., Hu, X. et al. Apoptosis (2006) 11: 1175. doi:10.1007/s10495-006-8048-9

Abstract

The proteasome inhibitors are a new class of antitumor agents. These inhibitors cause the accumulation of many proteins in the cell with the induction of apoptosis including TRAIL death receptors DR4 and DR5, but the role of the TRAIL apoptotic pathway in proteasome inhibitor cytotoxicity is unknown. Herein, we have demonstrated that the induction of apoptosis by the proteasome inhibitors, MG-132 and PS-341 (bortezomib, Velcade), in primary CLL cells and the Burkitt lymphoma cell line, BJAB, is associated with up-regulation of TRAIL and its death receptors, DR4 and DR5. In addition, FLICE-like inhibitory protein (c-FLIP) protein is decreased. MG-132 treatment increases binding of DR5 to the adaptor protein FADD, and causes caspase-8 activation and cleavage of pro-apoptotic BID. Moreover, DR4:Fc or blockage of DR4 and DR5 expression using RNA interference, which prevents TRAIL apoptotic signaling, blocks proteasome inhibitor induced apoptosis. MG-132 also increases apoptosis and DR5 expression in normal B-cells. However, when the proteasome inhibitors are combined with TRAIL or TRAIL receptor activating antibodies the amount of apoptosis is increased in CLL cells but not in normal B cells. Thus, activation of the TRAIL apoptotic pathway contributes to proteasome inhibitor induced apoptosis in CLL cells.

Keywords

Proteasome inhibitors TRAIL Death receptors Chronic lymphocytic leukemia Apoptosis B cells 

Copyright information

© Springer Science + Business Media, LLC 2006

Authors and Affiliations

  • Albert F. Kabore
    • 1
  • Jinmie Sun
    • 1
  • Xiaojie Hu
    • 1
  • Kristin McCrea
    • 1
  • James B. Johnston
    • 1
    • 2
  • Spencer B. Gibson
    • 1
    • 3
  1. 1.Manitoba Institute of Cell Biology, Cancer Care ManitobaUniversity of ManitobaWinnipeg
  2. 2.Department of Internal MedicineUniversity of ManitobaWinnipeg
  3. 3.Department of Biochemistry and Medical GeneticsUniversity of ManitobaWinnipeg