Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation

Hongbo Zhu, Wei Guo, Lidong Zhang, Shuhong Wu, Fuminori Teraishi, John J. Davis, Fengqin Dong, Bingliang Fang

Research output: Contribution to journalArticle

59 Citations (Scopus)

Abstract

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, Bel-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.

Original languageEnglish
Pages (from-to)781-786
Number of pages6
JournalCancer Biology and Therapy
Volume4
Issue number7
DOIs
Publication statusPublished - Jul 2005
Externally publishedYes

Keywords

  • Bik
  • Bortezomib
  • Death receptor 5
  • PS-341
  • Proteasome inhibitor
  • Resistance
  • Tumor necrosis factor-related apoptotic-inducing ligand (TRAIL)

ASJC Scopus subject areas

  • Molecular Medicine
  • Oncology
  • Pharmacology
  • Cancer Research

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