Src activation of Stat3 is an independent requirement from NF-¦ÊB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells
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- 作者：Jose G. Trevino ; Michael J. Gray ; Steffan T. Nawrocki ; Justin M. Summy ; Donald P. Lesslie ; Douglas B. Evans ; Tomi K. Sawyer ; William C. Shakespeare ; Stephanie S. Watowich and Paul J. Chiao ; et al.
- 关键词：Angiogenesis ; IL ; 8 ; Src ; NF ; κ ; B ; STAT3 ; NF ; kappaB ; Pancreatic adenocarcinoma
- 刊名：Angiogenesis
- 出版年：2006
- 出版时间：June, 2006
- 年：2006
- 卷：9
- 期：2
- 页码：101-110
- 全文大小：249 KB
文摘
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.