Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation

Cancer Biol Ther. 2005 Jul;4(7):781-6. doi: 10.4161/cbt.4.7.1897. Epub 2005 Jul 6.


Proteasome inhibitors can resensitize cells that are resistant to tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)-mediated apoptosis. However, the underlying mechanisms of this effect are unclear. To characterize the mechanisms of interaction between proteasome inhibitors and TRAIL protein, we evaluated the effects of combined treatment with the proteasome inhibitors bortezomib and MG132 and TRAIL protein on two TRAIL-resistant human colon cancer cell lines, DLD1-TRAIL/R and LOVO-TRAIL/R. Both bortezomib and MG132 in combination with TRAIL enhanced apoptotosis induction in these cells, as evidenced by enhanced cleavage of caspases 8, 9, and 3, Bid, poly(ADP-ribose) polymerase and by the release of cytochrome C and Smac. Subsequent studies showed that combined treatment with bortezomib or MG132 resulted in an increase of death receptor (DR) 5 and Bik at protein levels but had no effects on protein levels of DR4, Bax, Bak, Bcl-2, Bcl-XL or Flice-inhibitory protein (FLIP). Moreover, c-Jun N-terminal kinase (JNK) is activated by these proteasome inhibitors. Blocking JNK activation with the JNK inhibitor SP600125 attenuated DR5 increase, but enhancement of apoptosis induction and increase of Bik protein were not affected. However, bortezomib-mediated TRAIL sensitization was partially blocked by using siRNA to knockdown Bik. Thus, our data suggests that accumulation of Bik may be critical for proteasome inhibitor-mediated resensitization of TRAIL.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Apoptosis Regulatory Proteins / antagonists & inhibitors
  • Apoptosis Regulatory Proteins / genetics
  • Apoptosis Regulatory Proteins / metabolism*
  • BH3 Interacting Domain Death Agonist Protein / metabolism
  • Boronic Acids / pharmacology
  • Bortezomib
  • Caspases / metabolism
  • Cell Proliferation / drug effects
  • Colonic Neoplasms / drug therapy*
  • Colonic Neoplasms / metabolism
  • Cysteine Proteinase Inhibitors / pharmacology*
  • Cytochromes c / metabolism
  • Drug Resistance, Neoplasm*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism
  • Leupeptins / pharmacology
  • Membrane Glycoproteins / metabolism*
  • Membrane Proteins / antagonists & inhibitors
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mitochondrial Proteins / metabolism
  • Poly(ADP-ribose) Polymerases / metabolism
  • Proto-Oncogene Proteins c-bcl-2 / metabolism
  • Pyrazines / pharmacology
  • RNA, Small Interfering / pharmacology
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand
  • Tumor Cells, Cultured
  • Tumor Necrosis Factor-alpha / metabolism*
  • bcl-2-Associated X Protein / metabolism
  • bcl-X Protein / metabolism


  • Apoptosis Regulatory Proteins
  • BH3 Interacting Domain Death Agonist Protein
  • BIK protein, human
  • Boronic Acids
  • Cysteine Proteinase Inhibitors
  • DIABLO protein, human
  • Intracellular Signaling Peptides and Proteins
  • Leupeptins
  • Membrane Glycoproteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Proto-Oncogene Proteins c-bcl-2
  • Pyrazines
  • RNA, Small Interfering
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Tumor Necrosis Factor-alpha
  • bcl-2-Associated X Protein
  • bcl-X Protein
  • Bortezomib
  • Cytochromes c
  • Poly(ADP-ribose) Polymerases
  • Caspases
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde