Proteasome inhibition sensitizes hepatocellular carcinoma cells to TRAIL by suppressing caspase inhibitors and AKT pathway

Anticancer Drugs. 2006 Mar;17(3):261-8. doi: 10.1097/00001813-200603000-00004.

Abstract

The ubiquitin-proteasome pathway is responsible for regulating cell cycle proteins, tumor-suppressor molecules, oncogenes, transcription factors, and pro- and anti-apoptotic proteins. The aim of this study is to evaluate the effects of proteasome inhibitors on human hepatocellular carcinoma (HCC) cells. HCC cells SK-Hep1, HLE and HepG2 were treated with the proteasome inhibitors MG132 and MG115. Our data showed that both inhibitors induce apoptosis in the three cell types tested in a dose-dependent manner. Moreover, subtoxic levels of MG132 and MG115 sensitized HCC cells to TRAIL-induced apoptosis. To investigate the mechanism of increased TRAIL sensitivity in HCC cells, we first examined surface expression of TRAIL and its receptors. MG132 upregulated TRAIL and its receptors (TRAIL-R1 and -R2) in SK-Hep1 and HLE, whereas MG115 upregulated them in SK-Hep1. MG132 downregulated expression of X-linked inhibitor of apoptosis protein (XIAP) in SK-Hep1 and HLE, and of survivin in all three cell-types. MG115 downregulated expression of XIAP in SK-Hep1, and survivin in SK-Hep1 and HepG2. Furthermore, MG132 downregulated phospho-AKT and its downstream target phospho-BAD, indicating that MG132 activated the mitochondrial apoptosis pathway by inhibiting phosphorylation of AKT and BAD. In conclusion, proteasome inhibitors induced apoptosis and augmented TRAIL sensitivity via both the IAP family and AKT pathways. Thus, combining proteasome inhibitors with a TRAIL agonist may provide a new therapeutic strategy for HCC.

MeSH terms

  • Animals
  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects
  • Carcinoma, Hepatocellular / drug therapy*
  • Carcinoma, Hepatocellular / enzymology
  • Carcinoma, Hepatocellular / metabolism
  • Caspase Inhibitors*
  • Caspases / metabolism
  • Down-Regulation / drug effects
  • Drug Synergism
  • Humans
  • Leupeptins / pharmacology*
  • Mice
  • Oncogene Protein v-akt / antagonists & inhibitors*
  • Phosphorylation / drug effects
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors
  • Proto-Oncogene Proteins c-akt / metabolism*
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • Receptors, TNF-Related Apoptosis-Inducing Ligand / metabolism
  • Receptors, Tumor Necrosis Factor / biosynthesis
  • Receptors, Tumor Necrosis Factor / metabolism
  • TNF-Related Apoptosis-Inducing Ligand / biosynthesis
  • TNF-Related Apoptosis-Inducing Ligand / pharmacology*

Substances

  • Antineoplastic Agents
  • Caspase Inhibitors
  • Leupeptins
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Receptors, TNF-Related Apoptosis-Inducing Ligand
  • Receptors, Tumor Necrosis Factor
  • TNF-Related Apoptosis-Inducing Ligand
  • TNFRSF10A protein, human
  • TNFRSF10B protein, human
  • carbobenzoxy-leucyl-leucyl-norvalinal
  • Oncogene Protein v-akt
  • Proto-Oncogene Proteins c-akt
  • Caspases
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde