Document Detail


USP8 is a novel target for overcoming gefitinib resistance in lung cancer.
MedLine Citation:
PMID:  23748694     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
PURPOSE: Common treatment modalities for non-small cell lung cancer (NSCLC) involve the EGF receptor-tyrosine kinase inhibitors (EGFR-TKIs) like gefitinib and erlotinib. However, the vast majority of treated patients acquire resistance to EGFR-TKIs, due, in large part, to secondary mutations in EGFR or amplification of the MET gene. Our purpose was to test ubiquitin-specific peptidase 8 (USP8) as a potential therapeutic target for gefitinib-resistant and -sensitive non-small cell lung cancer (NSCLC).
EXPERIMENTAL DESIGN: Testing the effect of knockdown of USP8 and use of a synthetic USP8 inhibitor to selectively kill gefitinib-resistant (or -sensitive) NSCLCs with little effect on normal cells in cell culture and a xenograft mouse model.
RESULTS: Knockdown of ubiquitin-specific peptidase 8 (USP8) selectively kills gefitinib-resistant NSCLCs while having little toxicity toward normal cells. Genetic silencing of USP8 led to the downregulation of several receptor tyrosine kinases (RTK) including EGFR, ERBB2, ERBB3, and MET. We also determined that a synthetic USP8 inhibitor markedly decreased the viability of gefitinib-resistant and -sensitive NSCLC cells by decreasing RTK expression while having no effect on normal cells. Moreover, treatment with a USP8 inhibitor led to significant reductions in tumor size in a mouse xenograft model using gefitinib-resistant and -sensitive NSCLC cells.
CONCLUSIONS: Our results show for the first time that the inhibition of USP8 activity or reduction in USP8 expression can selectively kill NSCLC cells. We propose USP8 as a potential therapeutic target for gefitinib-resistant and -sensitive NSCLC cells.
Authors:
Sanguine Byun; Sung-Young Lee; Jihoon Lee; Chul-Ho Jeong; Lee Farrand; Semi Lim; Kanamata Reddy; Ji Young Kim; Mee-Hyun Lee; Hyong Joo Lee; Ann M Bode; Ki Won Lee; Zigang Dong
Related Documents :
24319254 - A novel small molecule inhibitor of deubiquitylating enzyme usp14 and uchl5 induces apo...
23034174 - Mesothelin regulates growth and apoptosis in pancreatic cancer cells through p53-depend...
24973724 - Bioengineering paradigms for cell migration in confined microenvironments.
18663224 - Nik overexpression amplifies, whereas ablation of its traf3-binding domain replaces baf...
437954 - X-like and y-like ganglion cells in the necturus retina.
6580524 - Regulation of the maximal rate of rna synthesis in the fission yeast schizosaccharomyce...
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2013-06-07
Journal Detail:
Title:  Clinical cancer research : an official journal of the American Association for Cancer Research     Volume:  19     ISSN:  1078-0432     ISO Abbreviation:  Clin. Cancer Res.     Publication Date:  2013 Jul 
Date Detail:
Created Date:  2013-07-17     Completed Date:  2014-02-05     Revised Date:  2014-07-20    
Medline Journal Info:
Nlm Unique ID:  9502500     Medline TA:  Clin Cancer Res     Country:  United States    
Other Details:
Languages:  eng     Pagination:  3894-904     Citation Subset:  IM    
Export Citation:
APA/MLA Format     Download EndNote     Download BibTex
MeSH Terms
Descriptor/Qualifier:
Animals
Antineoplastic Agents / pharmacology*
Carcinoma, Non-Small-Cell Lung / drug therapy*,  enzymology
Cell Line, Tumor
Cell Survival
Drug Resistance, Neoplasm*
Endopeptidases / genetics,  metabolism*
Endosomal Sorting Complexes Required for Transport / antagonists & inhibitors,  genetics,  metabolism*
Gene Expression Regulation, Neoplastic
Gene Knockdown Techniques
Humans
Lung Neoplasms / drug therapy*,  enzymology
Male
Mice
Mice, Nude
Protease Inhibitors / pharmacology
Quinazolines / pharmacology*
Receptor Protein-Tyrosine Kinases / genetics,  metabolism
Ubiquitin Thiolesterase / antagonists & inhibitors,  genetics,  metabolism*
Xenograft Model Antitumor Assays
Grant Support
ID/Acronym/Agency:
CA077646/CA/NCI NIH HHS; CA120388/CA/NCI NIH HHS; ES016548/ES/NIEHS NIH HHS; R01 CA077646/CA/NCI NIH HHS; R01 CA120388/CA/NCI NIH HHS; R01 ES016548/ES/NIEHS NIH HHS; R37 CA081064/CA/NCI NIH HHS; R37 CA081646/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/Antineoplastic Agents; 0/Endosomal Sorting Complexes Required for Transport; 0/Protease Inhibitors; 0/Quinazolines; 0/USP8 protein, human; EC 2.7.10.1/Receptor Protein-Tyrosine Kinases; EC 3.1.2.15/Ubiquitin Thiolesterase; EC 3.4.-/Endopeptidases; S65743JHBS/gefitinib
Comments/Corrections

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


Previous Document:  Observation learning of a motor task: who and when?
Next Document:  Molecular Pathways: PI3-kinase pathway targets in triple negative breast cancers.