Macroautophagy modulates cellular response to proteasome inhibitors in cancer therapy

Drug Resist Updat. 2010 Jun;13(3):87-92. doi: 10.1016/j.drup.2010.04.003. Epub 2010 May 11.

Abstract

Macroautophagy and the ubiquitin-proteasome system are two complementary pathways for protein degradation. The former degrades long-lived proteins and damaged organelles while the later degrades short-lived proteins. Recent findings indicate that suppression of the ubiquitin-proteasome system by proteasome inhibitors induces macroautophagy through multiple pathways, including (1) accumulation of ubiquitinated proteins and activation of HDAC6; (2) activation of the IRE1-JNK pathway; (3) proteasomal stabilization of ATF4; (4) inhibition of mTOR complex 1 signaling; (5) reduced proteasomal degradation of LC3. Induction of macroautophagy attenuates the antitumor effect of proteasome inhibitors in various types of cancer. These findings suggest that inhibition of macroautophagy may represent a novel strategy to enhance cellular sensitivity to proteasome inhibition.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Activating Transcription Factor 4 / metabolism
  • Antineoplastic Agents / therapeutic use*
  • Autophagy*
  • Boronic Acids / therapeutic use
  • Bortezomib
  • Endoribonucleases / metabolism
  • Histone Deacetylase 6
  • Histone Deacetylases / metabolism
  • Humans
  • JNK Mitogen-Activated Protein Kinases / metabolism
  • Mechanistic Target of Rapamycin Complex 1
  • Membrane Proteins / metabolism
  • Microtubule-Associated Proteins / metabolism
  • Multiprotein Complexes
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / physiopathology
  • Proteasome Inhibitors*
  • Protein-Serine-Threonine Kinases / metabolism
  • Proteins
  • Pyrazines / therapeutic use
  • Signal Transduction / drug effects
  • TOR Serine-Threonine Kinases
  • Transcription Factors / metabolism
  • Ubiquitinated Proteins / metabolism
  • Ubiquitins / antagonists & inhibitors*

Substances

  • ATF4 protein, human
  • Antineoplastic Agents
  • Boronic Acids
  • Membrane Proteins
  • Microtubule-Associated Proteins
  • Multiprotein Complexes
  • Proteasome Inhibitors
  • Proteins
  • Pyrazines
  • Transcription Factors
  • Ubiquitinated Proteins
  • Ubiquitins
  • light chain 3, human
  • Activating Transcription Factor 4
  • Bortezomib
  • ERN2 protein, human
  • TOR Serine-Threonine Kinases
  • Mechanistic Target of Rapamycin Complex 1
  • Protein-Serine-Threonine Kinases
  • JNK Mitogen-Activated Protein Kinases
  • Endoribonucleases
  • HDAC6 protein, human
  • Histone Deacetylase 6
  • Histone Deacetylases