Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria

Katalin Nagy, Kinga Székely-Szüts, Kamel Izeradjene, Leslie Douglas, Mike Tillman, Helga Barti-Juhász, Massimo Dominici, Carlotta Spano, Gian Luca Cervo, Pierfranco Conte, Janet A. Houghton, Rudolf Mihalik, László Kopper, István Peták

Research output: Contribution to journalArticlepeer-review

Abstract

The synergistic interaction between proteasome inhibitors and tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) is a promising approach to induce cell death in tumor cells. However, the molecular and biochemical mechanisms of this synergism have been proven to be cell type specific. We therefore focused our investigation on TRAIL-resistant colon carcinoma cells in this study. DNA fragmentation, mitochondrial membrane depolarization and increased caspase-3-like enzyme activity was exclusively induced only by combined treatment with proteasome inhibitors (epoxomicin, MG132, bortezomib/PS-341) and TRAIL. The expression level of anti-apoptotic proteins (XIAP, survivin, Bcl-2, Bcl-XL), regulated by NF-κB transcription factor, was not effected by any of these treatments. TRAIL alone induced only partial activation of caspase-3 (p20), while the combination of TRAIL and proteasome inhibition led to the full proteolytic activation of caspase-3 (p17). Only the combination treatment induced marked membrane depolarization and the release of cytochrome c, HtrA2/Omi and Smac/DIABLO. Apoptosis-inducing factor (AIF) was not released in any of these conditions. These results are consistent with a model where the full activation of caspase-3 by caspase-8 is dependent on the release of Smac/DIABLO in response to the combined treatment. This molecular mechanism, independent of the inhibition NF-kB activity, may provide rationale for the combination treatment of colon carcinomas with proteasome inhibitors and recombinant TRAIL or agonistic antibody of TRAIL receptors.

Original languageEnglish
Pages (from-to)133-142
Number of pages10
JournalPathology and Oncology Research
Volume12
Issue number3
Publication statusPublished - 2006

Keywords

  • Bortezomib/PS-341
  • Colon carcinoma
  • Epoxomicin
  • MG132
  • Smac/DIABLO
  • TRAIL

ASJC Scopus subject areas

  • Cancer Research
  • Oncology
  • Pathology and Forensic Medicine

Fingerprint

Dive into the research topics of 'Proteasome inhibitors sensitize colon carcinoma cells to TRAIL-induced apoptosis via enhanced release of Smac/DIABLO from the mitochondria'. Together they form a unique fingerprint.

Cite this