+1 Recommend
0 collections
      • Record: found
      • Abstract: found
      • Article: found
      Is Open Access

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


      Read this article at

          There is no author summary for this article yet. Authors can add summaries to their articles on ScienceOpen to make them more accessible to a non-specialist audience.



          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.


          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.


          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.

          Related collections

          Most cited references13

          • Record: found
          • Abstract: found
          • Article: not found

          Cleavage of BID by caspase 8 mediates the mitochondrial damage in the Fas pathway of apoptosis.

          We report here that BID, a BH3 domain-containing proapoptotic Bcl2 family member, is a specific proximal substrate of Casp8 in the Fas apoptotic signaling pathway. While full-length BID is localized in cytosol, truncated BID (tBID) translocates to mitochondria and thus transduces apoptotic signals from cytoplasmic membrane to mitochondria. tBID induces first the clustering of mitochondria around the nuclei and release of cytochrome c independent of caspase activity, and then the loss of mitochondrial membrane potential, cell shrinkage, and nuclear condensation in a caspase-dependent fashion. Coexpression of BclxL inhibits all the apoptotic changes induced by tBID. Our results indicate that BID is a mediator of mitochondrial damage induced by Casp8.
            • Record: found
            • Abstract: not found
            • Article: not found

            Targeting death and decoy receptors of the tumour-necrosis factor superfamily.

              • Record: found
              • Abstract: found
              • Article: not found

              Osteoprotegerin is a receptor for the cytotoxic ligand TRAIL.

              TRAIL is a tumor necrosis factor-related ligand that induces apoptosis upon binding to its death domain-containing receptors, DR4 and DR5. Two additional TRAIL receptors, TRID/DcR1 and DcR2, lack functional death domains and function as decoy receptors for TRAIL. We have identified a fifth TRAIL receptor, namely osteoprotegerin (OPG), a secreted tumor necrosis factor receptor homologue that inhibits osteoclastogenesis and increases bone density in vivo. OPG-Fc binds TRAIL with an affinity of 3.0 nM, which is slightly weaker than the interaction of TRID-Fc or DR5-Fc with TRAIL. OPG inhibits TRAIL-induced apoptosis of Jurkat cells. Conversely, TRAIL blocks the anti-osteoclastogenic activity of OPG. These data suggest potential cross-regulatory mechanisms by OPG and TRAIL.

                Author and article information

                Cancer Res Treat
                Cancer Research and Treatment : Official Journal of Korean Cancer Association
                Korean Cancer Association
                June 2011
                30 June 2011
                : 43
                : 2
                : 124-130
                [1 ]Division of Hematology-Oncology, Department of Internal Medicine and Institute for Clinical Molecular Biology Research, Soonchunhyang University College of Medicine, Seoul, Korea.
                [2 ]Catholic Research Institutes of Medical Science, The Catholic University of Korea School of Medicine, Seoul, Korea.
                [3 ]Division of Oncology, Department of Internal Medicine, Yeouido St. Mary's Hospital, The Catholic University of Korea School of Medicine, Seoul, Korea.
                [4 ]Division of Oncology, Department of Internal Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea School of Medicine, Incheon, Korea.
                Author notes
                Correspondence: Jae Ho Byun, MD, PhD. Division of Oncology, Incheon St. Mary's Hospital, The Catholic University of Korea School of Medicine, Bupyeong 6-dong, Bupyeong-gu, Incheon 403-720, Korea. Tel: 82-32-510-5797, Fax: 82-32-510-5683, jhbyun37@ 123456catholic.ac.kr
                Copyright © 2011 by the Korean Cancer Association

                This is an Open-Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                : 02 August 2010
                : 30 September 2010
                Original Article

                Oncology & Radiotherapy
                apoptosis,mg 132,tnf-related apoptosis-inducing ligand,soft tissue sarcoma


                Comment on this article