Induction of endoplasmic reticulum stress by bortezomib sensitizes myeloma cells to DR5-mediated cell death

DOI
  • MIKI Hirokazu
    Division of Transfusion and Cell Therapy Medicine, Tokushima University Hospital
  • NAKAMURA Shingen
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • ODA Asuka
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • AMACHI Ryota
    Department of Orthodontics and Dentofacial Orthopedics, The University of Tokushima Graduate School of Oral Science
  • WATANABE Keiichiro
    Department of Orthodontics and Dentofacial Orthopedics, The University of Tokushima Graduate School of Oral Science
  • HANSON Derek
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • TERAMACHI Jumpei
    Department of Histology and Oral Histology, The University of Tokushima Graduate School of Oral Science
  • HIASA Masahiro
    Department of Biomaterials and Bioengineering, The University of Tokushima Graduate School of Oral Science
  • YAGI Hikaru
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • SOGABE Kimiko
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • TAKAHASHI Mamiko
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • MARUHASHI Tomoko
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • UDAKA Kengo
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • HARADA Takeshi
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • FUJII Shiro
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • NAKANO Ayako
    Department of Internal Medicine, Naruto Hospital
  • KAGAWA Kumiko
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences
  • RI Masaki
    Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences
  • IIDA Shinsuke
    Department of Hematology and Oncology, Nagoya City University Graduate School of Medical Sciences
  • OZAKI Shuji
    Department of Hematology, Tokushima Prefectural Central Hospital
  • MATSUMOTO Toshio
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences Fujii Memorial Institute for Medical Reseach, The University of Tokushima
  • ABE Masahiro
    Department of Medicine and Bioregulatory Sciences, The University of Tokushima Graduate School of Health Biosciences

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<p>TNF-related apoptosis-including ligand/Apo2 (TRAIL)-mediated immunotherapy is an attractive anti-tumor modality with high tumor specificity. In order to improve its therapeutic efficacy, we further need to implement a novel maneuver for sensitization of malignant cells to TRAIL. Bortezomib (BTZ), a novel anti-myeloma (MM) agent, potently induces endoplasmic reticulum (ER) stress to cause apoptosis. Here, we explored the roles of BTZ in the cytotoxicity of anti-TRAIL receptor agonistic antibodies against MM cells with special reference to ER stress. BTZ enhanced the expression of death receptor 5 (DR5) but not DR4 in MM cells at surface protein as well as mRNA levels. However, the DR5 expression was not affected by BTZ without ER stress induction in MM cells with a point mutation in a BTZ-binding proteasome β5 subunit. Tunicamycin, an ER stress inducer, was able to enhance the DR5 expression even in the BTZ-resistant MM cells, suggesting the role of ER stress in up-regulation of DR5 expression. Interestingly, BTZ facilitated extrinsic caspase-mediated apoptosis by anti-DR5 agonistic antibody in MM cells along with reducing c-FLICE-like interleukin protein, a caspase 8 inhibitor. These results suggest that BTZ enhances DR5 expression and its downstream apoptotic signaling through ER stress to sensitize MM cells to TRAIL-mediated immunotherapy.</p>

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