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.
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.
Rodrigues
Sylvie
S
INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, 75571 Paris, France.
Attoub
Samir
S
Nguyen
Quang-Dé
QD
Bruyneel
Erik
E
Rodrigue
Christelle M
CM
Westley
Bruce R
BR
May
Felicity E B
FE
Thim
Lars
L
Mareel
Marc
M
Emami
Shahin
S
Gespach
Christian
C
D066258:Amphiregulin; D000818:Animals; D002478:Cells, Cultured; D003110:Colonic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D004285:Dogs; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors / Q000494:pharmacology; D004815:Epidermal Growth Factor / Q000378:metabolism / Q000494:pharmacology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000235:genetics / Q000378:metabolism*; D000077156:Gefitinib; D016391:Genes, src / Q000235:genetics; D006023:Glycoproteins / Q000378:metabolism / Q000494:pharmacology; D006133:Growth Substances / Q000378:metabolism / Q000494:pharmacology*; D006801:Humans; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism / Q000494:pharmacology; D007668:Kidney / Q000166:cytology / Q000187:drug effects / Q000378:metabolism*; D009077:Mucins; D009124:Muscle Proteins; D009154:Mutation; D009361:Neoplasm Invasiveness; D009479:Neuropeptides; D010455:Peptides / Q000378:metabolism / Q000494:pharmacology*; D019869:Phosphatidylinositol 3-Kinases / Q000187:drug effects / Q000378:metabolism; D011506:Proteins; D011799:Quinazolines / Q000494:pharmacology; D017482:Receptors, Thromboxane / Q000037:antagonists & inhibitors / Q000187:drug effects / Q000378:metabolism; D015398:Signal Transduction; D016211:Transforming Growth Factor alpha / Q000378:metabolism / Q000494:pharmacology; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins
C587848:AREG protein, human; D066258:Amphiregulin; C587850:Areg protein, rat; D066255:EGF Family of Proteins; D004791:Enzyme Inhibitors; D006023:Glycoproteins; D006133:Growth Substances; D036341:Intercellular Signaling Peptides and Proteins; D009077:Mucins; D009124:Muscle Proteins; D009479:Neuropeptides; D010455:Peptides; D011506:Proteins; D011799:Quinazolines; D017482:Receptors, Thromboxane; C051838:TFF1 protein, human; C099037:TFF3 protein, rat; C000604008:Tff2 protein, rat; D016211:Transforming Growth Factor alpha; D000071163:Trefoil Factor-1; D000071164:Trefoil Factor-2; D000071165:Trefoil Factor-3; D025521:Tumor Suppressor Proteins; D004815:Epidermal Growth Factor; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors; D000077156:Gefitinib