Selective abrogation of the proinvasive activity of the trefoil peptides pS2 and spasmolytic polypeptide by disruption of the EGF receptor signaling pathways in kidney and colonic cancer cells.

Abstract	Trefoil peptides (TFFs) are now considered as scatter factors, proinvasive and angiogenic agents acting through cyclooxygenase-2 (COX-2)- and thromboxane A2 receptor (TXA2-R)-dependent signaling pathways. As expression and activation levels of the epidermal growth factor receptor (EGFR) predict the metastatic potential of human colorectal cancers, the purpose of this study was to establish whether the EGF receptor tyrosine kinase (EGFR-TK) contributes to cellular invasion induced by TFFs in kidney and colonic cancer cells. Both the dominant negative form of the EGFR (HER-CD533) and the EGFR-TK inhibitor ZD1839 (Iressa) abrogated cellular invasion induced by pS2, spasmolytic polypeptide (SP) and the src oncogene, but not by ITF and the TXA2-R. Similarly, EGFR-TK inhibition by ZD1839 reversed the invasive phenotype promoted by the constitutively activated form of the EGFR (EGFRvIII) and the EGFR agonists transforming growth factor alpha (TGFalpha), amphiregulin and EGF. We also provide evidence that TFFs, EGFRvIII, and TGFalpha trigger common proinvasive pathways using the PI3'-kinase and Rho/Rho- kinase cascades. These findings identify the EGFR-TK as a key signaling element for pS2- and SP-mediated cellular invasion. It is concluded that although pS2, SP and ITF belong to the same family of inflammation- and cancer-associated regulatory peptides, they do not control identical signaling networks.
Authors	Sylvie Rodrigues, Samir Attoub, Quang-Dé Nguyen, Erik Bruyneel, Christelle M Rodrigue, Bruce R Westley, Felicity E B May, Lars Thim, Marc Mareel, Shahin Emami, Christian Gespach
Journal	Oncogene (Oncogene) Vol. 22 Issue 29 Pg. 4488-97 (Jul 17 2003) ISSN: 0950-9232 [Print] England
PMID	12881705 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
Chemical References	AREG protein, human Amphiregulin Areg protein, rat EGF Family of Proteins Enzyme Inhibitors Glycoproteins Growth Substances Intercellular Signaling Peptides and Proteins Mucins Muscle Proteins Neuropeptides Peptides Proteins Quinazolines Receptors, Thromboxane TFF1 protein, human TFF3 protein, rat Tff2 protein, rat Transforming Growth Factor alpha Trefoil Factor-1 Trefoil Factor-2 Trefoil Factor-3 Tumor Suppressor Proteins Epidermal Growth Factor Phosphatidylinositol 3-Kinases ErbB Receptors Gefitinib
Topics	Amphiregulin Animals Cells, Cultured Colonic Neoplasms (drug therapy, metabolism, pathology) Dogs EGF Family of Proteins Enzyme Inhibitors (pharmacology) Epidermal Growth Factor (metabolism, pharmacology) ErbB Receptors (antagonists & inhibitors, drug effects, genetics, metabolism) Gefitinib Genes, src (genetics) Glycoproteins (metabolism, pharmacology) Growth Substances (metabolism, pharmacology) Humans Intercellular Signaling Peptides and Proteins (metabolism, pharmacology) Kidney (cytology, drug effects, metabolism) Mucins Muscle Proteins Mutation Neoplasm Invasiveness Neuropeptides Peptides (metabolism, pharmacology) Phosphatidylinositol 3-Kinases (drug effects, metabolism) Proteins Quinazolines (pharmacology) Receptors, Thromboxane (antagonists & inhibitors, drug effects, metabolism) Signal Transduction Transforming Growth Factor alpha (metabolism, pharmacology) Trefoil Factor-1 Trefoil Factor-2 Trefoil Factor-3 Tumor Suppressor Proteins

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