Proteasome inhibitors-mediated TRAIL resensitization and Bik accumulation

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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs
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Chemical Inactivation of the E3 Ubiquitin Ligase Cereblon by Pomalidomide-based Homo-PROTACs

Published on: May 15, 2019

Hongbo Zhu1, Wei Guo, Lidong Zhang

  • 1Department of Surgical Oncology, Sir Run Run Shaw Hospital, Zhejiang University, China.

Cancer Biology & Therapy
|August 6, 2005
PubMed

Insights

Proteasome inhibitors resensitize cancer cells to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) therapy. Bik accumulation is critical for this resensitization, enhancing TRAIL-mediated apoptosis.

Area of Science:

  • Oncology
  • Molecular Biology
  • Cell Death Research

Background:

  • Proteasome inhibitors can overcome resistance to tumor necrosis factor-related apoptosis-inducing ligand (TRAIL)-mediated apoptosis.
  • The precise mechanisms underlying this resensitization remain incompletely understood.

Purpose of the Study:

  • To elucidate the interaction mechanisms between proteasome inhibitors and TRAIL.
  • To investigate how proteasome inhibitors resensitize TRAIL-resistant colon cancer cells.

Main Methods:

  • Treatment of TRAIL-resistant colon cancer cell lines (DLD1-TRAIL/R, LOVO-TRAIL/R) with bortezomib/MG132 and TRAIL.
  • Analysis of apoptosis markers (caspase cleavage, cytochrome C, Smac release).
  • Assessment of death receptor and apoptosis regulator protein levels (DR5, Bik, DR4, Bax, Bak, Bcl-2, Bcl-XL, FLIP).
  • Investigation of c-Jun N-terminal kinase (JNK) pathway involvement and Bik knockdown using siRNA.

Main Results:

  • Combined bortezomib/MG132 and TRAIL treatment enhanced apoptosis induction and caspase cleavage.
  • Proteasome inhibitors increased protein levels of death receptor 5 (DR5) and Bik, but not other regulators.
  • JNK activation by proteasome inhibitors influenced DR5 levels but not apoptosis enhancement or Bik increase.
  • Bik knockdown partially blocked bortezomib-mediated TRAIL sensitization.

Conclusions:

  • Accumulation of Bik protein is a key factor in proteasome inhibitor-mediated resensitization to TRAIL.
  • This study clarifies a crucial mechanism for overcoming TRAIL resistance in cancer therapy.

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