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The NF-κB pathway down-regulates expression of the NKG2D ligand H60a in vitro: implications for use of NF-κB inhibitors in cancer therapy.
MedLine Citation:
PMID:  23350962     Owner:  NLM     Status:  Publisher    
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 tumor cells express high levels of NKG2D ligands, they are rejected by the immune system. Thus, reagents that increase NKG2D ligand expression on tumor cells can be important for tumor immunotherapy. To identify genes that regulate the NKG2D ligand H60a, we performed a microarray analysis of 3'methylcholanthrene (MCA)-induced sarcoma cell lines expressing high versus low H60a levels. We found that A20, an inhibitor of NF-κB activation, was differentially expressed in H60a-hi sarcoma cells. Correspondingly, treatment of tumor 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-beta (IKKβ) led to decreased levels of H60a. The regulation likely occurred at the transcriptional level, since NF-κB pathway inhibition led to increased H60a transcripts and promoter activity. Moreover, treatment of tumor cells with slz enhanced their killing by natural killer (NK) cells in vitro, suggesting that NF-κB inhibition can lead to tumor cell rejection. Indeed, when we blocked the NF-κB pathway specifically in tumor cells, there was decreased tumor growth in WT but not immune deficient mice. Our results suggest that reagents that can block NF-κB activity specifically in the tumor and not the host immune cells would be efficacious for tumor therapy. © 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
Authors:
Carlos Peinado; Xi Kang; Chanae Hardamon; Sumit Arora; Stephen Mah; Hui Zhang; Jennifer Ngolab; Jack D Bui
Publication Detail:
Type:  JOURNAL ARTICLE     Date:  2013-1-28
Journal Detail:
Title:  Immunology     Volume:  -     ISSN:  1365-2567     ISO Abbreviation:  Immunology     Publication Date:  2013 Jan 
Date Detail:
Created Date:  2013-1-28     Completed Date:  -     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0374672     Medline TA:  Immunology     Country:  -    
Other Details:
Languages:  ENG     Pagination:  -     Citation Subset:  -    
Copyright Information:
© 2013 The Authors. Immunology © 2013 Blackwell Publishing Ltd.
Affiliation:
Department of Pathology, University of California, San Diego, La Jolla, CA, 92093.
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