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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

Oncogene volume 22, pages 4488–4497 (2003)Cite this article

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 (TGFα), amphiregulin and EGF. We also provide evidence that TFFs, EGFRvIII, and TGFα 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.

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Acknowledgements

This work was supported by INSERM, Aventis Pharma (France), AstraZeneca, Research Grants from I'Association de la Recherche sur le Cancer (ARC, France), and the Fortis Bank, Verzekeringen (Brussels, Belgium). ZD1839 (IRESSA), kindly provided by AstraZeneca (Macclesfield, United Kingdom), is a trademark of the AstraZeneca group of companies. SR is a PhD student supported by the French Ministry of Scientific Research.

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Authors and Affiliations

  1. INSERM U482, Signal Transduction and Cellular Functions in Diabetes and Digestive Cancers, Hôpital Saint-Antoine, Paris, Cedex 12, 75571, France

    Sylvie Rodrigues, Samir Attoub, Quang-Dé Nguyen, Christelle M Rodrigue, Shahin Emami & Christian Gespach

  2. Laboratory of Experimental Cancerology, Ghent University Hospital, Ghent, B-900, Belgium

    Erik Bruyneel & Marc Mareel

  3. Department of Pathology, University of Newcastle, Newcastle upon Tyne, NE1 4LP, UK

    Bruce R Westley & Felicity E B May

  4. Novo Nordisk, Bagsvaerd, DK-2880, Denmark

    Lars Thim

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  1. Sylvie Rodrigues
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Rodrigues, S., Attoub, S., Nguyen, QD. et al. 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. Oncogene 22, 4488–4497 (2003). https://doi.org/10.1038/sj.onc.1206685

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