A novel inhibitor of proteasome deubiquitinating activity renders tumor cells sensitive to TRAIL-mediated apoptosis by natural killer cells and T cells

Cancer Immunol Immunother. 2013 Aug;62(8):1359-68. doi: 10.1007/s00262-013-1439-1. Epub 2013 May 21.


The proteasome inhibitor bortezomib simultaneously renders tumor cells sensitive to killing by natural killer (NK) cells and resistant to killing by tumor-specific T cells. Here, we show that b-AP15, a novel inhibitor of proteasome deubiquitinating activity, sensitizes tumors to both NK and T cell-mediated killing. Exposure to b-AP15 significantly increased the susceptibility of tumor cell lines of various origins to NK (p < 0.0002) and T cell (p = 0.02)-mediated cytotoxicity. Treatment with b-AP15 resulted in increased tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) receptor-2 expression (p = 0.03) and decreased cFLIP expression in tumor cells in vitro. In tumor-bearing SCID/Beige mice, treatment with b-AP15 followed by infusion of either human NK cells or tumor-specific T cells resulted in a significantly delayed tumor progression compared with mice treated with NK cells (p = 0.006), T cells (p < 0.0001) or b-AP15 alone (p = 0.003). Combined infusion of NK and T cells in tumor-bearing BALB/c mice following treatment with b-AP15 resulted in a significantly prolonged long-term survival compared with mice treated with b-AP15 and NK or T cells (p ≤ 0.01). Our findings show that b-AP15-induced sensitization to TRAIL-mediated apoptosis could be used as a novel strategy to augment the anticancer effects of adoptively infused NK and T cells in patients with cancer.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Apoptosis / immunology*
  • Blotting, Western
  • Cell Line, Tumor
  • Cells, Cultured
  • Combined Modality Therapy
  • Cytokines / immunology
  • Cytokines / metabolism
  • Cytotoxicity, Immunologic / drug effects
  • Cytotoxicity, Immunologic / immunology
  • HCT116 Cells
  • HeLa Cells
  • Humans
  • Immunotherapy, Adoptive
  • K562 Cells
  • Killer Cells, Natural / immunology*
  • Killer Cells, Natural / metabolism
  • Killer Cells, Natural / transplantation
  • MCF-7 Cells
  • Mice
  • Mice, Inbred BALB C
  • Mice, SCID
  • Neoplasms / immunology*
  • Neoplasms / pathology
  • Neoplasms / therapy
  • Piperidones / immunology*
  • Piperidones / pharmacology
  • Protease Inhibitors / immunology*
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex / immunology*
  • Proteasome Endopeptidase Complex / metabolism
  • T-Lymphocytes / immunology*
  • T-Lymphocytes / metabolism
  • T-Lymphocytes / transplantation
  • TNF-Related Apoptosis-Inducing Ligand / immunology
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology
  • Ubiquitination / drug effects
  • Xenograft Model Antitumor Assays


  • 3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one
  • Cytokines
  • Piperidones
  • Protease Inhibitors
  • TNF-Related Apoptosis-Inducing Ligand
  • Proteasome Endopeptidase Complex