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c‐Src‐mediated interleukin‐8 overexpression and migration of endothelial cells: implications in PCB‐mediated tumor metastasis
Author(s) -
Eum Sung Yong,
Rha Geun Bae,
Bernhard Hennig,
Toborek Michal
Publication year - 2006
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.20.5.a1147-c
Subject(s) - angiogenesis , autocrine signalling , proto oncogene tyrosine protein kinase src , endothelial stem cell , chemistry , microbiology and biotechnology , signal transduction , cancer research , biology , receptor , biochemistry , in vitro
The aim of the present study was to study the regulatory mechanisms of IL‐8 induced by ortho‐substituted PCBs. IL‐8 is a prominent factor that modulates endothelial cell proliferation, migration and angiogenesis. Treatment of human microvascular endothelial cells (HMEC) with 2,2¡ ¯ ,4,6,6¡ ¯ ‐pentachlorobiphenyl (PCB 104), a highly ortho‐substituted non‐coplanar PCB congener, increased levels of IL‐8 mRNA and secreted protein. In addition, IL‐8‐neutralizing antibody inhibited migration of endothelial cells stimulated by condition media derived from PCB 104‐treated HMEC. Site‐directed mutagenesis of the IL‐8 promoter and DNA binding assay with IL‐8 specific sequence revealed that AP‐1 and NF‐kB are required for PCB 104‐induced IL‐8 transcription. Both inhibition of c‐Src kinase and overexpression of a dominant negative c‐Src caused a significant decrease in IL‐8 expression. In contrast, overexpression of activated c‐Src markedly increased the promoter activity of IL‐8. Mutagenesis of AP‐1 or NF‐kB binding sites abrogated the c‐Src‐mediated an increase in IL‐8 promoter activity. These data indicate that c‐Src may regulate crucial downstream signaling pathways leading to overexpression of IL‐8 in PCB 104‐treated HMEC. Thus, induction of the IL‐8 autocrine pathway may contribute to environmental pollutant‐induced tumor progression and/or metastasis formation. Supported by NIH/NIEHS (P42 ES 07380).