Proteasome inhibition induces both pro- and anti-cell death pathways in prostate cancer cells

Cancer Lett. 2006 Nov 18;243(2):217-27. doi: 10.1016/j.canlet.2005.11.033. Epub 2006 Jan 18.

Abstract

The proteasome-mediated protein degradation is critical for regulation of a variety of cellular processes, including cell cycle, cell death, differentiation and immune response. Proteasome inhibitors have recently been shown to be potent anti-cancer agents against a variety of cancer cells. Our study demonstrated that proteasome inhibitor MG132 (carbobenzoxy-L-leucyle-L-leucyl-L-leucinal) was a potent death-inducing agent for PC3 prostate cancer cells. MG132-induced cell death was partially inhibited by pan-caspase inhibitor zAVD-fmk and translational inhibitor cycloheximide. To understand the signaling pathways of proteasome inhibitor-induced cell death, we performed gene profiling study using Affymetrix human DNA microarrays to identify the genes whose expression was affected by proteasome inhibitor MG132 in PC3 cells. The genes with more than threefold increased expression induced by MG132 were functionally categorized into the following groups: heat shock and chaperone proteins, ubiquitination and protein degradation, transcription/translation factors, cell death and cell cycle arrest, signaling molecules and enzymes, and secreted cytokines. Among them, heat shock proteins and anti-oxidant enzymes may promote cell survival, while pro-death proteins such as GADD45B and STK17a may promote cell death. Interestingly, expression of a few autophagic genes was elevated by MG132 treatment. Furthermore, autophagy inhibitor 3-methyladenine partially inhibited MG132-induced cell death, indicating that autophagic cell death may contribute to MG132-induced cell death. Taken together, our results demonstrated that proteasome inhibition elicits activation of multiple signaling pathways in prostate cancer cells.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Chloromethyl Ketones / pharmacology
  • Apoptosis / drug effects*
  • Apoptosis / genetics
  • Autophagy / drug effects
  • Autophagy / genetics
  • Caspase Inhibitors
  • Caspases / metabolism
  • Cell Line, Tumor
  • Cycloheximide / pharmacology
  • Cysteine Proteinase Inhibitors / pharmacology
  • Cytokines / genetics
  • Dose-Response Relationship, Drug
  • Gene Expression Profiling
  • Gene Expression Regulation, Neoplastic / drug effects
  • Heat-Shock Proteins / genetics
  • Humans
  • Intercellular Signaling Peptides and Proteins / genetics
  • Leupeptins / pharmacology*
  • Male
  • Microscopy, Electron
  • Molecular Chaperones / genetics
  • Oligonucleotide Array Sequence Analysis
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms / pathology
  • Prostatic Neoplasms / ultrastructure
  • Proteasome Endopeptidase Complex / metabolism
  • Proteasome Inhibitors*
  • Protein Synthesis Inhibitors / pharmacology
  • Signal Transduction / drug effects*
  • Signal Transduction / genetics

Substances

  • Amino Acid Chloromethyl Ketones
  • Caspase Inhibitors
  • Cysteine Proteinase Inhibitors
  • Cytokines
  • Heat-Shock Proteins
  • Intercellular Signaling Peptides and Proteins
  • Leupeptins
  • Molecular Chaperones
  • Proteasome Inhibitors
  • Protein Synthesis Inhibitors
  • benzyloxycarbonylvalyl-alanyl-aspartyl fluoromethyl ketone
  • Cycloheximide
  • Caspases
  • Proteasome Endopeptidase Complex
  • benzyloxycarbonylleucyl-leucyl-leucine aldehyde