Prostaglandin E2 receptor EP1 transactivates EGFR/MET receptor tyrosine kinases and enhances invasiveness in human hepatocellular carcinoma cells.

Abstract

Recent evidence indicates that cyclooxygenase-2 (COX-2) and epidermal growth factor receptor (EGFR) are involved in hepatocarcinogenesis. This study was designed to evaluate the possible interaction between the COX-2 and EGFR signaling pathways in human hepatocellular carcinoma (HCC) cells. Immunohistochemical analysis using serial sections of human HCC tissues revealed positive correlation between COX-2 and EGFR in HCC cells (P < 0.01). Overexpression of COX-2 in cultured HCC cells (Hep3B) or treatment with PGE(2) or the selective EP(1) receptor agonist, ONO-DI-004, increased EGFR phosphorylation and tumor cell invasion. The PGE(2)-induced EGFR phosphorylation and cell invasiveness were blocked by the EP(1) receptor siRNA or antagonist ONO-8711 and by two EGFR tyrosine kinase inhibitors, AG1478 and PD153035. The EP(1)-induced EGFR transactivation and cell invasion involves c-Src, in light of the presence of native binding complex of EP(1)/Src/EGFR and the inhibition of PGE(2)-induced EGFR phosphorylation and cell invasion by the Src siRNA and the Src inhibitor, PP2. Further, overexpression of COX-2 or treatment with PGE(2) also induced phosphorylation of c-Met, another receptor tyrosine kinase critical for HCC cell invasion. Moreover, activation of EGFR by EGF increased COX-2 promoter activity and protein expression in Hep3B and Huh-7 cells, whereas blocking PGE(2) synthesis or EP(1) attenuated EGFR phosphorylation induced by EGF, suggesting that the COX-2/PGE(2)/EP(1) pathway also modulate the activation of EGFR by its cognate ligand. These findings disclose a cross-talk between the COX-2/PGE(2)/EP(1) and EGFR/c-Met signaling pathways that coordinately regulate human HCC cell invasion.

• Authors: Chang Han, George K Michalopoulos, Tong Wu
• Journal: Journal of cellular physiology (J Cell Physiol) Vol. 207 Issue 1 Pg. 261-70 (Apr 2006) ISSN: 0021-9541 [Print] United States
• PMID: 16331686 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Retracted Publication)

Chemical References

• Bridged Bicyclo Compounds
• Caproates
• Membrane Proteins
• ONO 8711
• ONO-DI-004
• PTGER1 protein, human
• Protein Kinase Inhibitors
• Proto-Oncogene Proteins
• RNA, Small Interfering
• Receptors, Prostaglandin
• Receptors, Prostaglandin E
• Receptors, Prostaglandin E, EP1 Subtype
• Cyclooxygenase 2
• PTGS2 protein, human
• ErbB Receptors
• Protein-Tyrosine Kinases
• Proto-Oncogene Proteins c-met
• CSK Tyrosine-Protein Kinase
• src-Family Kinases
• CSK protein, human
• Alprostadil
• Dinoprostone

Topics

• Alprostadil (analogs & derivatives, pharmacology)
• Bridged Bicyclo Compounds (pharmacology)
• CSK Tyrosine-Protein Kinase
• Caproates (pharmacology)
• Carcinoma, Hepatocellular (genetics, metabolism, pathology)
• Cell Line, Tumor
• Cell Movement (drug effects, physiology)
• Cyclooxygenase 2 (analysis, genetics, metabolism)
• Dinoprostone (pharmacology)
• Enzyme Activation
• ErbB Receptors (antagonists & inhibitors, metabolism)
• Gene Expression (genetics)
• Humans
• Liver Neoplasms (genetics, metabolism, pathology)
• Membrane Proteins (analysis, genetics, metabolism)
• Neoplasm Invasiveness
• Phosphorylation (drug effects)
• Protein Binding (drug effects)
• Protein Kinase Inhibitors (pharmacology)
• Protein-Tyrosine Kinases (metabolism)
• Proto-Oncogene Proteins (metabolism)
• Proto-Oncogene Proteins c-met (metabolism)
• RNA Interference
• RNA, Small Interfering (genetics)
• Receptors, Prostaglandin (genetics, metabolism)
• Receptors, Prostaglandin E (genetics, physiology)
• Receptors, Prostaglandin E, EP1 Subtype
• Transfection
• src-Family Kinases