| Autor: |
Trevino, Jose, Gray, Michael, Nawrocki, Steffan, Summy, Justin, Lesslie, Donald, Evans, Douglas, Sawyer, Tomi, Shakespeare, William, Watowich, Stephanie, Chiao, Paul, McConkey, David, Gallick, Gary |
| Zdroj: |
Angiogenesis; June 2006, Vol. 9 Issue: 2 p101-110, 10p |
| Abstrakt: |
Human pancreatic tumors often overexpress the angiogenesis-promoting factor Interleukin 8 (IL-8), in part due to overexpression of NF-κB, a frequent occurrence in pancreatic adenocarcinoma. In this study, we demonstrate that reducing c-Src kinase activity, through either pharmacologic inhibition or small interfering RNA-targeted reduction of Src expression, significantly decreased IL-8 expression (P< 0.05) without affecting NF-κB-mediated transcription, but by decreasing phosphorylation of STAT3. To ascertain whether Src-mediated expression of IL-8 was dependent on STAT3, we used stable clones expressing a dominant-negative isoform of STAT3 that inhibits endogenous STAT3 phosphorylation and subsequent DNA binding and STAT3-mediated gene expression or a constitutively activated isoform of STAT3. IL-8 expression was significantly lower in clones expressing the dominant-negative isoform and significantly increased in clones expressing the activated isoform (P< 0.05 for both). Pharmacologic inhibition of NF-κB activity significantly reduced basal IL-8 expression and tumor necrosis factor-induced IL-8 expression (P< 0.05 for both), yet NF-κB activity was not dependent on Src. We therefore suggest that Src activation, through phosphorylation of␣STAT3, and NF-κB are all required for expression of IL-8 a critical angiogenic-promoting factor in pancreatic adenocarcinomas.Human pancreatic tumors often overexpress the angiogenesis-promoting factor Interleukin 8 (IL-8), in part due to overexpression of NF-κB, a frequent occurrence in pancreatic adenocarcinoma. In this study, we demonstrate that reducing c-Src kinase activity, through either pharmacologic inhibition or small interfering RNA-targeted reduction of Src expression, significantly decreased IL-8 expression (P< 0.05) without affecting NF-κB-mediated transcription, but by decreasing phosphorylation of STAT3. To ascertain whether Src-mediated expression of IL-8 was dependent on STAT3, we used stable clones expressing a dominant-negative isoform of STAT3 that inhibits endogenous STAT3 phosphorylation and subsequent DNA binding and STAT3-mediated gene expression or a constitutively activated isoform of STAT3. IL-8 expression was significantly lower in clones expressing the dominant-negative isoform and significantly increased in clones expressing the activated isoform (P< 0.05 for both). Pharmacologic inhibition of NF-κB activity significantly reduced basal IL-8 expression and tumor necrosis factor-induced IL-8 expression (P< 0.05 for both), yet NF-κB activity was not dependent on Src. We therefore suggest that Src activation, through phosphorylation of␣STAT3, and NF-κB are all required for expression of IL-8 a critical angiogenic-promoting factor in pancreatic adenocarcinomas. |
| Databáze: |
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