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

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.

journal_name

Angiogenesis

journal_title

Angiogenesis

authors

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

doi

10.1007/s10456-006-9038-9

subject

Has Abstract

pub_date

2006-01-01 00:00:00

pages

101-10

issue

2

eissn

0969-6970

issn

1573-7209

journal_volume

9

pub_type

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