Interplay between epidermal growth factor receptor and Janus kinase 3 regulates polychlorinated biphenyl-induced matrix metalloproteinase-3 expression and transendothelial migration of tumor cells.

Abstract

We hypothesize that environmental toxicants, such as polychlorinated biphenyl congeners, can activate vascular endothelial cells and thus increase formation of blood-borne metastases. This study indicates that exposure of human microvascular endothelial cells to 2,2',4,6,6'-pentachlorobiphenyl can stimulate transendothelial migration of tumor cells through up-regulation of matrix metalloproteinase (MMP)-3. In a series of experiments with specific small interfering RNA and pharmacologic inhibitors, we provide evidence that 2,2',4,6,6'-pentachlorobiphenyl can activate epidermal growth factor receptor (EGFR) and Janus kinase 3 (JAK3) in a closely coordinated and cross-dependent fashion. Activated EGFR and JAK3 stimulate in concert c-Jun NH(2)-terminal kinase and extracellular signal-regulated kinase 1/2 as well as increase DNA-binding activity of transcription factors activator protein-1 and polyomavirus enhancer activator protein 3, leading to transcriptional up-regulation of MMP-3 expression. These results indicate that the interplay among EGFR, JAK3, and mitogen-activated protein kinases, such as c-Jun NH(2)-terminal kinase and extracellular signal-regulated kinase 1/2, is critical for polychlorinated biphenyl-induced MMP-3 expression and accelerated transendothelial migration of tumor cells.

• Authors: Sung Yong Eum, Yong Woo Lee, Bernhard Hennig, Michal Toborek
• Journal: Molecular cancer research : MCR (Mol Cancer Res) Vol. 4 Issue 6 Pg. 361-70 (Jun 2006) ISSN: 1541-7786 [Print] United States
• PMID: 16778083 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• DNA-Binding Proteins
• Transcription Factor AP-1
• Transcription Factors
• enhancer-binding protein AP-3
• Polychlorinated Biphenyls
• ErbB Receptors
• Protein-Tyrosine Kinases
• JAK3 protein, human
• Janus Kinase 3
• Mitogen-Activated Protein Kinases
• Matrix Metalloproteinase 3
• 2,2',4,6,6'-pentachlorobiphenyl

Topics

• Breast Neoplasms (metabolism, pathology)
• Capillary Permeability
• Cell Adhesion
• Cell Line, Tumor
• Cell Movement
• DNA-Binding Proteins (metabolism)
• Endothelial Cells (drug effects, enzymology)
• Endothelium, Vascular (drug effects)
• ErbB Receptors (metabolism)
• Humans
• Janus Kinase 3
• Matrix Metalloproteinase 3 (genetics)
• Mitogen-Activated Protein Kinases
• Neoplasm Metastasis
• Polychlorinated Biphenyls (metabolism, toxicity)
• Protein-Tyrosine Kinases (metabolism)
• Transcription Factor AP-1 (metabolism)
• Transcription Factors (metabolism)
• Up-Regulation