Src activation of Stat3 is an independent requirement from NF-κB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells

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, Paul J. Chiao, David J. McConkey, Gary E. Gallick

Research output: Contribution to journalArticle

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 languageEnglish (US)
Pages (from-to)101-110
Number of pages10
JournalAngiogenesis
Volume9
Issue number2
DOIs
StatePublished - Jun 1 2006
Externally publishedYes

Keywords

  • Angiogenesis
  • IL-8
  • NF-kappaB
  • NF-κB
  • Pancreatic adenocarcinoma
  • STAT3
  • Src

ASJC Scopus subject areas

  • Physiology
  • Clinical Biochemistry
  • Cancer Research

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  • Cite this

    Trevino, J. G., Gray, M. J., Nawrocki, S. T., Summy, J. M., Lesslie, D. P., Evans, D. B., Sawyer, T. K., Shakespeare, W. C., Watowich, S. S., Chiao, P. J., McConkey, D. J., & Gallick, G. E. (2006). Src activation of Stat3 is an independent requirement from NF-κB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis, 9(2), 101-110. https://doi.org/10.1007/s10456-006-9038-9