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    
Abstract/OtherAbstract:
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.
Authors:
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
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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    
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MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Apoptosis / drug effects
Boronic Acids / pharmacology*
Cell Line, Tumor
Drug Resistance, Neoplasm / drug effects
Endoplasmic Reticulum Stress / drug effects
Female
Gene Expression Regulation, Neoplastic
Humans
Mice
Multiple Myeloma / drug therapy*,  genetics,  pathology
Piperidones / pharmacology*
Protease Inhibitors / pharmacology*
Pyrazines / pharmacology*
Ubiquitin Thiolesterase / antagonists & inhibitors*,  genetics
Up-Regulation
Grant Support
ID/Acronym/Agency:
P01 CA078378/CA/NCI NIH HHS; P01 CA078378/CA/NCI NIH HHS; P50100707//PHS HHS; R01 CA050947/CA/NCI NIH HHS
Chemical
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 3.1.2.15/USP14 protein, human; EC 3.1.2.15/Ubiquitin Thiolesterase; EC 3.4.19.12/UCHL5 protein, human

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


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