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Assays for the Degradation of Misfolded Proteins in Cells
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Assays for the Degradation of Misfolded Proteins in Cells

Published on: August 28, 2016

Proteasome inhibitors disrupt the unfolded protein response in myeloma cells

Ann-Hwee Lee1, Neal N Iwakoshi, Kenneth C Anderson

  • 1Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02115-6017, USA.

Proceedings of the National Academy of Sciences of the United States of America
|August 7, 2003
PubMed

Insights

Proteasome inhibitors, used for multiple myeloma, disrupt the unfolded protein response (UPR) by targeting XBP-1. This mechanism leads to myeloma cell death, suggesting new therapeutic strategies for UPR-dependent cancers.

Area of Science:

  • Molecular Biology
  • Cancer Biology
  • Cellular Signaling

Background:

  • Proteasome inhibitors show efficacy in multiple myeloma but their mechanism is unclear.
  • The unfolded protein response (UPR) pathway regulates protein folding and is crucial for plasma cell differentiation.
  • X-box binding protein 1 (XBP-1) is a key regulator of the UPR and plasma cell development.

Purpose of the Study:

  • To elucidate the mechanism of action for proteasome inhibitors in multiple myeloma.
  • To investigate the role of the UPR and XBP-1 in mediating proteasome inhibitor efficacy.
  • To identify potential therapeutic targets within the IRE1 alpha/XBP-1 pathway.

Main Methods:

  • Treatment of myeloma cells with proteasome inhibitors.
  • Analysis of XBP-1 splicing and stability.
  • Assessment of endoplasmic reticulum stress and apoptosis induction.
  • Inhibition of IRE1 alpha activity.

Main Results:

  • Proteasome inhibitors suppress IRE1 alpha activity, impairing spliced XBP-1 generation and stabilizing unspliced XBP-1.
  • Myeloma cells with deficient XBP-1 function exhibit increased apoptosis under endoplasmic reticulum stress.
  • The UPR pathway is a critical target of proteasome inhibitors in myeloma cells.

Conclusions:

  • Proteasome inhibitors exert their therapeutic effect by targeting the IRE1 alpha/XBP-1 axis of the UPR.
  • Dysregulation of the UPR pathway is a key vulnerability in multiple myeloma.
  • Targeting IRE1 alpha/XBP-1 presents a promising therapeutic strategy for multiple myeloma and other UPR-dependent malignancies.

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