Pathology & Oncology Research

, 12:133

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
Article

DOI: 10.1007/BF02893359

Cite this article as:
Nagy, K., Székely-Szüts, K., Izeradjene, K. et al. Pathol. Oncol. Res. (2006) 12: 133. doi:10.1007/BF02893359

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. (Pathology Oncology Research Vol 12, No 3, 133–142)

Key words

TRAIL epoxomicin MG132 bortezomib/PS-341 Smac/DIABLO colon carcinoma 

Abbreviations

Ac-DEVD-AMC

Ac-Asp-Glu-Val-Asp-7-amino-4-methyl-coumarin

z-VAD-fmk

benzyloxycarbonyl-Val-Ala-Asp (OMe)-fluoromethylketone

z-IETD-fmk

benzyloxycarbonyl-Ile-Glu(OMe)-Thr-Asp (OMe)-fluoromethylketone

MG132

ben-zyloxycarbonyl-Leu-Leu-Leu-aldehyde

AIF

apoptosis-inducing factor

IAP

inhibitor of apoptosis protein

XIAP

X-linked IAP

Epo

epoxomicin

Copyright information

© Arányi Lajos Foundation 2006

Authors and Affiliations

  • Katalin Nagy
    • 1
    • 3
  • Kinga Székely-Szüts
    • 5
  • Kamel Izeradjene
    • 5
  • Leslie Douglas
    • 5
  • Mike Tillman
    • 5
  • Helga Barti-Juhász
    • 1
  • Massimo Dominici
    • 4
  • Carlotta Spano
    • 4
  • Gian Luca Cervo
    • 4
  • Pierfranco Conte
    • 4
  • Janet A Houghton
    • 5
  • Rudolf Mihalik
    • 2
  • László Kopper
    • 1
    • 2
    • 3
  • István Peták
    • 1
    • 3
  1. 1.1st Department of Pathology and Experimental Cancer ResearchSemmelweis UniversityBudapestHungary
  2. 2.Molecular Pathology Research GroupJoint Research Organization of the Hungarian Academy of Science and Semmelweis UniversityBudapest
  3. 3.Szentágothai János Knowledge CenterBudapestHungary
  4. 4.Department of Oncology and HematologyUniversity of Modena and Reggio EmiliaModenaItaly
  5. 5.Division of Molecular Therapeutics, Department of Hematology-OncologySt. Jude Children’s Research HospitalMemphisUSA