Document Detail


The nuclear factor-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of nuclear factor-κB inhibitors in cancer therapy.
MedLine Citation:
PMID:  23350962     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
NKG2D ligands are cell surface proteins that activate NKG2D, a receptor used by natural killer (NK) cells to detect virus-infected and transformed cells. When tumour cells express high levels of NKG2D ligands, they are rejected by the immune system. Hence, reagents that increase NKG2D ligand expression on tumour cells can be important for tumour immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3'-methylcholanthrene-induced sarcoma cell lines expressing high versus low H60a levels. A20, an inhibitor of nuclear factor-κB (NF-κB) activation, was differentially expressed in H60a-hi sarcoma cells. Correspondingly, treatment of tumour cells with inhibitors of NF-κB activation, such as sulfasalazine (slz), BAY-11-7085, or a non-phosphorylatable IκB, led to increased levels of H60a protein, whereas transduction of cells with an active form of IκB kinase-β (IKKβ) led to decreased levels of H60a. The regulation probably occurred at the transcriptional level, because NF-κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumour cells with slz enhanced their killing by NK cells in vitro, suggesting that NF-κB inhibition can lead to tumour cell rejection. Indeed, when we blocked the NF-κB pathway specifically in tumour cells, there was decreased tumour growth in wild-type but not immune-deficient mice. Our results suggest that reagents that can block NF-κB activity specifically in the tumour and not the host immune cells would be efficacious for tumour therapy.
Authors:
Carlos Peinado; Xi Kang; Chanae Hardamon; Sumit Arora; Stephen Mah; Hui Zhang; Jennifer Ngolab; Jack D Bui
Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't    
Journal Detail:
Title:  Immunology     Volume:  139     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 Jun 
Date Detail:
Created Date:  2013-04-24     Completed Date:  2013-07-01     Revised Date:  2014-06-03    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  England    
Other Details:
Languages:  eng     Pagination:  265-74     Citation Subset:  IM    
Copyright Information:
© 2013 Blackwell Publishing Ltd.
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MeSH Terms
Descriptor/Qualifier:
Animals
Cell Line, Tumor
Cytotoxicity, Immunologic / drug effects
DNA-Binding Proteins / genetics,  metabolism
Down-Regulation
Flow Cytometry
Gene Expression Profiling
Gene Expression Regulation, Neoplastic / drug effects
I-kappa B Kinase / genetics,  metabolism
I-kappa B Proteins / genetics,  metabolism
Intracellular Signaling Peptides and Proteins / genetics,  metabolism
Killer Cells, Natural / drug effects,  metabolism
Mice
Mice, 129 Strain
Mice, Inbred C57BL
Minor Histocompatibility Antigens / genetics*,  metabolism
Mutation
NF-kappa B / genetics*,  metabolism
NK Cell Lectin-Like Receptor Subfamily K / genetics*,  metabolism
Neoplasms / drug therapy,  genetics,  metabolism
Oligonucleotide Array Sequence Analysis
Reverse Transcriptase Polymerase Chain Reaction
Signal Transduction / drug effects,  genetics*
Sulfasalazine / pharmacology
Ubiquitin-Protein Ligases / genetics,  metabolism
Grant Support
ID/Acronym/Agency:
CA128893/CA/NCI NIH HHS; CA157885/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/DNA-Binding Proteins; 0/I-kappa B Proteins; 0/Intracellular Signaling Peptides and Proteins; 0/Minor Histocompatibility Antigens; 0/NF-kappa B; 0/NK Cell Lectin-Like Receptor Subfamily K; 0/minor H antigen H60; 139874-52-5/NF-kappaB inhibitor alpha; 3XC8GUZ6CB/Sulfasalazine; EC 2.7.11.10/I-kappa B Kinase; EC 6.3.2.19/A20 protein, mouse; EC 6.3.2.19/Ubiquitin-Protein Ligases
Comments/Corrections

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