Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells.

Abstract

The 26S proteasome inhibitor, bortezomib, has shown remarkable therapeutic efficacy in multiple myeloma (MM), however, the mechanism by which this compound acts remains unknown. Here, we have demonstrated that bortezomib targets the prototypical expression of unfolded protein response (UPR) genes BiP, CHOP and XBP-1 at the mRNA and protein levels, resulting in induction of proapoptotic UPR outputs and suppression of cytoprotective UPR components, leading to caspase-dependent apoptosis in human MM H929 and 8226/S cell lines. Moreover, knockdown of XPB-1s, via lentivirus-mediated RNA interference approach, sensitises MM cells to apoptosis induction by bortezomib. Together, these data strongly suggest that dysregulated or disruptive UPR may, at least partly, underlie the antimyeloma activity of bortezomib.

• Authors: Hongjuan Dong, Liang Chen, Xiequn Chen, Hongtao Gu, Guangxun Gao, Ying Gao, Baoxia Dong
• Journal: Leukemia & lymphoma (Leuk Lymphoma) Vol. 50 Issue 6 Pg. 974-84 (Jun 2009) ISSN: 1029-2403 [Electronic] United States
• PMID: 19391038 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Boronic Acids
• DDIT3 protein, human
• DNA-Binding Proteins
• Endoplasmic Reticulum Chaperone BiP
• Heat-Shock Proteins
• Protease Inhibitors
• Pyrazines
• Regulatory Factor X Transcription Factors
• Transcription Factors
• X-Box Binding Protein 1
• XBP1 protein, human
• Transcription Factor CHOP
• Brefeldin A
• Thapsigargin
• Bortezomib

Topics

• Apoptosis (drug effects)
• Blotting, Western
• Boronic Acids (pharmacology)
• Bortezomib
• Brefeldin A (pharmacology)
• Cell Line, Tumor
• Cell Proliferation (drug effects)
• DNA-Binding Proteins (chemistry, genetics, metabolism)
• Dose-Response Relationship, Drug
• Endoplasmic Reticulum (metabolism)
• Endoplasmic Reticulum Chaperone BiP
• Gene Expression (drug effects)
• Heat-Shock Proteins (chemistry, genetics, metabolism)
• Humans
• Protease Inhibitors (pharmacology)
• Pyrazines (pharmacology)
• RNA Interference
• Regulatory Factor X Transcription Factors
• Reverse Transcriptase Polymerase Chain Reaction
• Thapsigargin (pharmacology)
• Transcription Factor CHOP (chemistry, genetics, metabolism)
• Transcription Factors (chemistry, genetics, metabolism)
• X-Box Binding Protein 1