The discovery of NO donors as immunosensitizing agents was inadvertently found by examining the mechanism underlying the regulation of Fas expression by interferon-g and sensitization of Fas ligand resistant tumors to Fas ligand-induced apoptosis. Treatment with interferon-g induced the expression of NOSII and treatment with NO donors mimicked interferon-g. Hence, we hypothesized that NO may inhibit a transcription repressor that regulates Fas transcription and resulting in upregulation of Fas and sensitization to Fas ligand-induced apoptosis. We have found that YY1 negatively regulates Fas transcription and that NO inhibits YY1 DNA-binding activity [44, 57, 58]. Further, we demonstrated that NO modified YY1 into an S-nitrosylated form that inhibited its DNA-binding activity . Further studies identified a YY1-DNA binding activity in the silencer region of the Fas promoter . Subsequent studies revealed that YY1 also regulates the transcription of the TRAIL-receptor DR5 and inhibition of YY1 by NO or siRNA upregulates DR5 and sensitized the tumor cells to TRAIL-induced apoptosis . The role of NO donors as sensitizing agents for immunotherapy of cancer is an attractive approach provided that NO levels are appropriate for sensitization. Further, NO administration can also affect angiogenesis. Further details on the role of NO and cancer have been recently reviewed .
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