Faculty Collaboration Database

Src activation of Stat3 is an independent requirement from NF-kappaB activation for constitutive IL-8 expression in human pancreatic adenocarcinoma cells. Angiogenesis 2006;9(2):101-10

Date

07/28/2006

Pubmed ID

16871430

DOI

10.1007/s10456-006-9038-9

Scopus ID

2-s2.0-33748982652 (requires institutional sign-in at Scopus site)   46 Citations

Abstract

Human pancreatic tumors often overexpress the angiogenesis-promoting factor Interleukin 8 (IL-8), in part due to overexpression of NF-kappaB, 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-kappaB-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-kappaB activity significantly reduced basal IL-8 expression and tumor necrosis factor-induced IL-8 expression (P < 0.05 for both), yet NF-kappaB activity was not dependent on Src. We therefore suggest that Src activation, through phosphorylation of STAT3, and NF-kappaB are all required for expression of IL-8 a critical angiogenic-promoting factor in pancreatic adenocarcinomas.

Author List

Trevino JG, Gray MJ, Nawrocki ST, Summy JM, Lesslie DP, Evans DB, Sawyer TK, Shakespeare WC, Watowich SS, Chiao PJ, McConkey DJ, Gallick GE

Author

Douglas B. Evans MD Chair, Professor in the Surgery department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Adenocarcinoma
Cell Line, Tumor
Genes, Reporter
Humans
Immunohistochemistry
Interleukin-8
Luciferases
Microscopy, Confocal
NF-kappa B
Pancreatic Neoplasms
Phosphorylation
Proto-Oncogene Proteins pp60(c-src)
RNA, Small Interfering
STAT3 Transcription Factor