Journal
MOLECULAR CANCER RESEARCH
Volume 9, Issue 10, Pages 1356-1365Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1541-7786.MCR-11-0185
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Funding
- National Research Foundation (NRF) of Korea
- Ministry of Education, Science and Technology [2009-0072161]
- Korea Research Foundation
- Korean Government (MOEHRD) [KRF-211-2005-1-E00007]
- National Research Foundation of Korea [2009-0072161] Funding Source: Korea Institute of Science & Technology Information (KISTI), National Science & Technology Information Service (NTIS)
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IFN-gamma plays a critical role in tumor immunosurveillance by affecting either immune cells or tumor cells; however, IFN-mediated effects on tumor elimination are largely unknown. In this study, we showed that IFN regulatory factors (IRF) modulated by IFNs up- and downregulated Noxa expression, a prodeath BH3 protein, in various cancer cells. Inhibition of Noxa expression using short hairpin RNA in tumor cells leads to resistance against lipopolysaccharide (LPS)-induced tumor elimination, in which IFN-gamma is known as a critical effecter in mice. Chromatin immunoprecipitation analysis in both CT26 cells and SP2/0 cells, sensitive and resistant to LPS-induced tumor elimination, respectively, revealed that the responsiveness of IRF1, 3, 4, and 7 in the Noxa promoter region in response to IFN-gamma might be crucial in LPS-induced tumor elimination. IRF1, 3, and 7 were upregulated by IFN-gamma and activated Noxa expression, leading to the death of Noxa wild-type baby mouse kidney (BMK) cells but not of Noxa-deficient BMK cells. In contrast, IRF4 acts as a repressor for Noxa expression and inhibits cell death induced by IRF1, 3, or 7. Therefore, although IFN-gamma alone are not able to induce cell death in tumor cells in vitro, Noxa induction by IFN-gamma, which is regulated by the balance between its activators (IRF1, 3, and 7) and its repressor (IRF4), is crucial to increasing the susceptibility of tumor cells to immune cell-mediated cytotoxicity. Mol Cancer Res; 9(10); 1356-65. (C) 2011 AACR.
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