Dysregulation of unfolded protein response partially underlies proapoptotic activity of bortezomib in multiple myeloma cells.
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.
Dong
Hongjuan
H
Department of Hematology, Xijing Hospital, Fourth Military Medical University, Xi'an, People's Republic of China.
Chen
Liang
L
Chen
Xiequn
X
Gu
Hongtao
H
Gao
Guangxun
G
Gao
Ying
Y
Dong
Baoxia
B
D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D001897:Boronic Acids / Q000494:pharmacology*; D000069286:Bortezomib; D020126:Brefeldin A / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D004268:DNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000378:metabolism; D000091342:Endoplasmic Reticulum Chaperone BiP; D015870:Gene Expression / Q000187:drug effects; D006360:Heat-Shock Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D011480:Protease Inhibitors / Q000494:pharmacology; D011719:Pyrazines / Q000494:pharmacology*; D034622:RNA Interference; D000071701:Regulatory Factor X Transcription Factors; D020133:Reverse Transcriptase Polymerase Chain Reaction; D019284:Thapsigargin / Q000494:pharmacology; D051742:Transcription Factor CHOP / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D014157:Transcription Factors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D000071717:X-Box Binding Protein 1
D001897:Boronic Acids; C497249:DDIT3 protein, human; D004268:DNA-Binding Proteins; D000091342:Endoplasmic Reticulum Chaperone BiP; D006360:Heat-Shock Proteins; D011480:Protease Inhibitors; D011719:Pyrazines; D000071701:Regulatory Factor X Transcription Factors; D014157:Transcription Factors; D000071717:X-Box Binding Protein 1; C000605543:XBP1 protein, human; D051742:Transcription Factor CHOP; D020126:Brefeldin A; D019284:Thapsigargin; D000069286:Bortezomib