Proteasome inhibitor PS-341 induces apoptosis through induction of endoplasmic reticulum stress-reactive oxygen species in head and neck squamous cell carcinoma cells

Mol Cell Biol. 2004 Nov;24(22):9695-704. doi: 10.1128/MCB.24.22.9695-9704.2004.

Abstract

PS-341, also known as Velcade or Bortezomib, represents a new class of anticancer drugs which has been shown to potently inhibit the growth and/or progression of human cancers, including head and neck squamous cell carcinoma (HNSCC). Although it has been logically hypothesized that NF-kappaB is a major target of PS-341, the underlying mechanism by which PS-341 inhibits tumor cell growth is unclear. Here we found that PS-341 potently activated the caspase cascade and induced apoptosis in human HNSCC cell lines. Although PS-341 could inhibit NF-kappaB activation, the inhibition of NF-kappaB was not sufficient to initiate apoptosis in HNSCC cells. Using biochemical and microarray approaches, we found that proteasome inhibition by PS-341 induced endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) in HNSCC cells. The inhibition of ROS significantly suppressed caspase activation and apoptosis induced by PS-341. Consistently, PS-341 could not induce the ER stress-ROS in PS-341-resistant HNSCC cells. Taken together, our results suggest that in addition to the abolishment of the prosurvival NF-kappaB, PS-341 might directly induce apoptosis by activating proapoptotic ER stress-ROS signaling cascades in HNSCC cells, providing novel insights into the PS-341-mediated antitumor activity.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antineoplastic Agents / pharmacology*
  • Apoptosis / drug effects*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Carcinoma, Squamous Cell / drug therapy*
  • Carcinoma, Squamous Cell / genetics
  • Carcinoma, Squamous Cell / metabolism*
  • Carcinoma, Squamous Cell / pathology
  • Caspases / metabolism
  • Cell Line, Tumor
  • Endoplasmic Reticulum / drug effects
  • Endoplasmic Reticulum / metabolism
  • Gene Expression Profiling
  • Head and Neck Neoplasms / drug therapy*
  • Head and Neck Neoplasms / genetics
  • Head and Neck Neoplasms / metabolism*
  • Head and Neck Neoplasms / pathology
  • Humans
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism
  • Oligonucleotide Array Sequence Analysis
  • Protease Inhibitors / pharmacology*
  • Proteasome Endopeptidase Complex
  • Proteasome Inhibitors
  • Pyrazines / pharmacology*
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • NF-kappa B
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • Reactive Oxygen Species
  • Bortezomib
  • Caspases
  • Proteasome Endopeptidase Complex
  • ATP dependent 26S protease