Proteasome inhibitor MG132 potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells via DR5-dependent pathway

Oncol Rep. 2016 Aug;36(2):845-52. doi: 10.3892/or.2016.4839. Epub 2016 May 27.

Abstract

TRAIL is a tumor-selective apoptosis-inducing cytokine playing a vital role in the surveillance and elimination of some tumor cells. However, some tumors are resistant to TRAIL treatment. Proteasome inhibitor MG132 exhibits anti-proliferative and pro-apoptotic properties in many tumors. In this study, we demonstrated that proteasome inhibitor MG132 in vitro and in vivo potentiates TRAIL-induced apoptosis in gallbladder carcinoma GBC-SD cells. MG132 was able to inhibit the proliferation of GBC-SD cells and induce apoptosis in a dose-dependent manner. The induction of apoptosis by proteasome inhibitor MG132 was mainly through the extrinsic apoptotic pathways of caspase activation such as caspase-8, caspase-3 and PARP cleavage. In addition, this process was also dependent on the upregulation of death receptor 5 (DR5), which promoted TRAIL-induced apoptosis in GBC-SD cells. Taken together, these findings indicate that MG132 possesses anti-gallbladder cancer potential that correlate with regulation of DR5-dependent pathway, and suggest that MG132 may be a promising agent for sensitizing GBC-SD cells to TRAIL-induced apoptosis.

MeSH terms

  • Apoptosis / drug effects*
  • Apoptosis Regulatory Proteins / metabolism
  • Carcinoma / drug therapy*
  • Carcinoma / metabolism
  • Caspase 3 / metabolism
  • Caspase 8 / metabolism
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Gallbladder / drug effects
  • Gallbladder Neoplasms / drug therapy*
  • Gallbladder Neoplasms / metabolism
  • Humans
  • Leupeptins / pharmacology*
  • Proteasome Inhibitors / pharmacology*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • TNF-Related Apoptosis-Inducing Ligand / metabolism*
  • Up-Regulation / drug effects

Substances

  • Apoptosis Regulatory Proteins
  • Leupeptins
  • Proteasome Inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10B protein, human
  • TNFSF10 protein, human
  • Caspase 3
  • Caspase 8
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde