Document Detail

A novel small molecule inhibitor of deubiquitylating enzyme USP14 and UCHL5 induces apoptosis in multiple myeloma and overcomes bortezomib resistance.
MedLine Citation:
PMID:  24319254     Owner:  NLM     Status:  MEDLINE    
Proteasome inhibitors have demonstrated that targeting protein degradation is effective therapy in multiple myeloma (MM). Here we show that deubiquitylating enzymes (DUBs) USP14 and UCHL5 are more highly expressed in MM cells than in normal plasma cells. USP14 and UCHL5 short interfering RNA knockdown decreases MM cell viability. A novel 19S regulatory particle inhibitor b-AP15 selectively blocks deubiquitylating activity of USP14 and UCHL5 without inhibiting proteasome activity. b-AP15 decreases viability in MM cell lines and patient MM cells, inhibits proliferation of MM cells even in the presence of bone marrow stroma cells, and overcomes bortezomib resistance. Anti-MM activity of b-AP15 is associated with growth arrest via downregulation of CDC25C, CDC2, and cyclin B1 as well as induction of caspase-dependent apoptosis and activation of unfolded protein response. In vivo studies using distinct human MM xenograft models show that b-AP15 is well tolerated, inhibits tumor growth, and prolongs survival. Combining b-AP15 with suberoylanilide hydroxamic acid, lenalidomide, or dexamethasone induces synergistic anti-MM activity. Our preclinical data showing efficacy of b-AP15 in MM disease models validates targeting DUBs in the ubiquitin proteasomal cascade to overcome proteasome inhibitor resistance and provides the framework for clinical evaluation of USP14/UCHL5 inhibitors to improve patient outcome in MM.
Ze Tian; Padraig D'Arcy; Xin Wang; Arghya Ray; Yu-Tzu Tai; Yiguo Hu; Ruben D Carrasco; Paul Richardson; Stig Linder; Dharminder Chauhan; Kenneth C Anderson
Related Documents :
24803654 - Migrating cells mediate long-range wnt signaling.
24836754 - Automated single cell microbioreactor for monitoring intracellular dynamics and cell gr...
24792554 - The listeria cell wall and associated carbohydrate polymers.
23649634 - Hox antisense lincrna hoxa-as2 is an apoptosis repressor in all trans retinoic acid tre...
16668434 - Tracing cell wall biogenesis in intact cells and plants : selective turnover and altera...
16005854 - Depletion of 4-hydroxynonenal in hgsta4-transfected hle b-3 cells results in profound c...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-12-06
Journal Detail:
Title:  Blood     Volume:  123     ISSN:  1528-0020     ISO Abbreviation:  Blood     Publication Date:  2014 Jan 
Date Detail:
Created Date:  2014-01-31     Completed Date:  2014-03-26     Revised Date:  2014-05-15    
Medline Journal Info:
Nlm Unique ID:  7603509     Medline TA:  Blood     Country:  United States    
Other Details:
Languages:  eng     Pagination:  706-16     Citation Subset:  AIM; IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Boronic Acids / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Endoplasmic Reticulum Stress / drug effects
Gene Expression Regulation, Neoplastic
Multiple Myeloma / drug therapy*,  genetics,  pathology
Piperidones / pharmacology*
Protease Inhibitors / pharmacology*
Pyrazines / pharmacology*
Ubiquitin Thiolesterase / antagonists & inhibitors*,  genetics
Grant Support
P01 CA078378/CA/NCI NIH HHS; P01 CA078378/CA/NCI NIH HHS; P50100707//PHS HHS; R01 CA050947/CA/NCI NIH HHS
Reg. No./Substance:
0/3,5-bis((4-nitrophenyl)methylidene)-1-prop-2-enoylpiperidin-4-one; 0/Antineoplastic Agents; 0/Boronic Acids; 0/Piperidones; 0/Protease Inhibitors; 0/Pyrazines; 0/bortezomib; EC protein, human; EC Thiolesterase; EC protein, human

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine

Previous Document:  Cancer-associated thrombosis.
Next Document:  The CCAAT box-binding transcription factor NF-YA1 controls rhizobial infection.