Cancer Res Treat.  2011 Jun;43(2):124-130.

Up-regulation of the DR5 Expression by Proteasome Inhibitor MG132 Augments TRAIL-Induced Apoptosis in Soft Tissue Sarcoma Cell Lines

Affiliations
  • 1Division of Hematology-Oncology, Department of Internal Medicine and Institute for Clinical Molecular Biology Research, Soonchunhyang University College of Medicine, Seoul, Korea.
  • 2Catholic Research Institutes of Medical Science, The Catholic University of Korea School of Medicine, Seoul, Korea.
  • 3Division of Oncology, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea.
  • 4Division of Oncology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea School of Medicine, Incheon, Korea. jhbyun37@catholic.ac.kr

Abstract

PURPOSE
Current chemotherapeutics for treating locally advanced or metastatic soft tissue sarcomas (STS) are limited. Accordingly, the present in vitro study was conducted to evaluate the effects of treatment of STS cells with tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) applied as a single agent or in combination with a proteasome inhibitor, MG132.
MATERIALS AND METHODS
Sensitivity to TRAIL and activity of TRAIL-induced apoptotic pathways were analyzed in four STS cell lines: HTB-82 (rhabdomyosarcoma), HT-1080 (fibrosarcoma), HTB-93 (synovial sarcoma), and HTB-94 (chondrosarcoma). Reduction of the dye dimethylthiazolyl 2,5 diphenyltetrazolium bromide (MTT) was used to evaluate cytotoxic activity; western blots were used to evaluate TRAIL-induced apoptosis.
RESULTS
TRAIL induced apoptosis in HTB-93 cells, but had little effect in HTB-82, HT-1080, or HTB-94 cells. Expression of TRAIL receptor-1 and -2 did not correlate with sensitivity to TRAIL. Co-incubation of cells with TRAIL and a proteasome inhibitor, MG132, augmented the apoptotic effect of TRAIL in both TRAIL-sensitive and TRAIL-resistant cells. This effect was due to up-regulation of TRAIL receptors and members of the pro-apoptotic BCL-2 family by MG132.
CONCLUSION
These data show that combining TRAIL with MG132 enhances apoptosis and overcomes TRAIL resistance. This restoration of TRAIL sensitivity occurs through an increase in the expression of death receptor 5 and of pro-apoptotic BCL-2 family members such as BAX.

Keyword

TNF-related apoptosis-inducing ligand; MG 132; Soft tissue sarcoma; Apoptosis

MeSH Terms

Apoptosis
Blotting, Western
Cell Line
Humans
Leupeptins
Necrosis
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Receptors, TNF-Related Apoptosis-Inducing Ligand
Sarcoma
TNF-Related Apoptosis-Inducing Ligand
Up-Regulation
Leupeptins
Proteasome Endopeptidase Complex
Proteasome Inhibitors
Receptors, TNF-Related Apoptosis-Inducing Ligand
TNF-Related Apoptosis-Inducing Ligand
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