Abstract
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.
Original language | English (US) |
---|---|
Pages (from-to) | 101-110 |
Number of pages | 10 |
Journal | Angiogenesis |
Volume | 9 |
Issue number | 2 |
DOIs | |
State | Published - Jun 2006 |
Externally published | Yes |
Keywords
- Angiogenesis
- IL-8
- NF-kappaB
- NF-κB
- Pancreatic adenocarcinoma
- STAT3
- Src
ASJC Scopus subject areas
- Physiology
- Clinical Biochemistry
- Cancer Research