Journal
CANCER RESEARCH
Volume 68, Issue 5, Pages 1546-1554Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/0008-5472.CAN-07-2973
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Funding
- Medical Research Council [G0601165, G9800943] Funding Source: Medline
- MRC [G0601165, G9800943] Funding Source: UKRI
- Medical Research Council [G0601165, G9800943] Funding Source: researchfish
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The interaction of the activating receptor NKG2D with its ligands plays an important role in immunosurveillance of tumors and infectious pathogens, but dysregulation of this system may lead to autoimmunity. The expression of NKG2D ligands is induced by cellular stress. However, the regulation of expression of these molecules is not well understood. Here, we show that cells treated with proteasome inhibitors can become more susceptible to cytotoxicity mediated by natural killer cells because of the induction of expression of ligands for NKG2D, specifically ULBP2, but not down-regulation of MHC class I. Treatment with proteasome inhibitors led to up-regulation of ULBP2 expression in multiple, but not all, cell lines tested. This increase in expression of ULBP2 at the cell surface correlated with induction of transcription of the ULBP2 gene and synthesis of ULBP2 protein. In contrast, treatment with inhibitors of histone deacetylases led to increased levels of mRNA and protein, for both ULBP2 and MHC class I-related chain A/B molecules. Thus, different types of stress can trigger up-regulated expression of different sets of NKG2D ligands. Proteasome inhibitors are proving to be of significant value in the treatment of hematologic malignancies and these observations may help to better understand the biology of therapy with these compounds.
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