Proteasome inhibitors disrupt the unfolded protein response in myeloma cells.

Abstract

Novel agents that target the proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, have demonstrated remarkable therapeutic efficacy in multiple myeloma, a plasma cell malignancy. However, the mechanism by which these compounds act remains unknown. A signaling pathway called the unfolded protein response (UPR) allows cells to handle the proper folding of proteins. The transcription factor XBP-1, a regulator of the UPR, is also required for plasma cell differentiation, suggesting a link between the UPR and plasma cell differentiation. Here we show that proteasome inhibitors target XBP-1 and the UPR in myeloma cells. Proteasome inhibitors suppress the activity of the translumenal endoplasmic reticulum endoribonuclease/kinase, IRE1 alpha, to impair the generation of the active, spliced XBP-1 species and simultaneously stabilize the unspliced species that acts as a dominant negative. Myeloma cells rendered functionally deficient in XBP-1 undergo increased apoptosis in response to endoplasmic reticulum stress. Identification of compounds that target the activity of IRE1 alpha/XBP-1 may yield novel therapies for the treatment of multiple myeloma and other malignancies that rely on an intact UPR.

• Authors: Ann-Hwee Lee, Neal N Iwakoshi, Kenneth C Anderson, Laurie H Glimcher
• Journal: Proceedings of the National Academy of Sciences of the United States of America (Proc Natl Acad Sci U S A) Vol. 100 Issue 17 Pg. 9946-51 (Aug 19 2003) ISSN: 0027-8424 [Print] United States
• PMID: 12902539 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Cysteine Proteinase Inhibitors
• DNA-Binding Proteins
• Leupeptins
• Membrane Proteins
• Multienzyme Complexes
• Neoplasm Proteins
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Xbp1 protein, mouse
• Tunicamycin
• ERN2 protein, human
• Ern2 protein, mouse
• Protein Serine-Threonine Kinases
• Endoribonucleases
• Cysteine Endopeptidases
• Proteasome Endopeptidase Complex
• benzyloxycarbonylleucyl-leucyl-leucine aldehyde

Topics

• 3T3 Cells
• Animals
• Apoptosis (drug effects)
• Cysteine Endopeptidases
• Cysteine Proteinase Inhibitors (pharmacology)
• DNA-Binding Proteins (genetics, metabolism)
• Endoplasmic Reticulum (drug effects)
• Endoribonucleases
• Humans
• Leupeptins (pharmacology)
• Membrane Proteins
• Mice
• Multienzyme Complexes (antagonists & inhibitors)
• Multiple Myeloma (drug therapy, genetics, metabolism)
• Neoplasm Proteins (genetics, metabolism)
• Proteasome Endopeptidase Complex
• Protein Folding
• Protein Serine-Threonine Kinases (metabolism)
• RNA Splicing (drug effects)
• Regulatory Factor X Transcription Factors
• Transcription Factors (genetics, metabolism)
• Tumor Cells, Cultured
• Tunicamycin (pharmacology)
• X-Box Binding Protein 1