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EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity

Oncogene volume 31, pages 3457–3466 (2012)Cite this article

Abstract

In this report we describe the contribution of prostaglandin E2 (PGE2) derived from the inducible microsomal PGE-synthase type-1 (mPGES-1) to the epidermal growth factor receptor (EGFR) oncogenic drive in tumor epithelial cells and in tumor-bearing mice. EGFR stimulation upregulated expression of mPGES-1 in HT-29, A431 and A549 cancer cells. Egr-1, a transcription factor induced by EGF, mediated this response. The Egr-1 rise provoked the overexpression of mPGES-1 messenger and protein, and enhanced PGE2 formation. These changes were suppressed either by silencing Egr-1, or by upstream blockade of EGFR or ERK1/2 signals. Further, in a clonogenic assay on tumor cells, EGF induced a florid tumorigenic phenotype, which regressed when mPGES-1 was silenced or knocked down. EGF-induced mPGES-1 overexpression in epithelial cell reduced E-cadherin expression, whereas enhancing that of vimentin, suggesting an incipient mesenchymal phenotype. Additionally, inhibiting the EGFR in mice bearing the A431 tumor, the mPGES-1 expression and the tumor growth, exhibited a parallel decline. In conclusion, these findings provide novel evidence that a tight cooperation between the EGF/EGFR and mPGES-1 leads to a significant tumorigenic gain in epithelial cells, and provide clues for controlling the vicious association.

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Acknowledgements

We thank Dr MD Díaz-Muñoz for the construction of mPGES-1 plasmids. This work has received financial support from the Associazione Italiana della Ricerca sul Cancro (AIRC) IG10731 (MZ), Istituto Toscano Tumori (ITT) (SD), Comunidad de Madrid S-SAL2006/0015, Ministerio de Ciencia e Innovación SAF2010-18733 (MF), Ministerio de Ciencia e Innovación BFU2010-21055 (MAI).

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Author notes

  1. S Donnini and F Finetti: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Biotechnology, Section of Pharmacology, University of Siena, and Istituto Toscano Tumori (ITT), Siena, Italy

    S Donnini, F Finetti, E Terzuoli, A Giachetti & M Ziche

  2. Centro de Biologıa Molecular Severo Ochoa (CSIC UAM), Universidad Autónoma de Madrid, Madrid, Spain

    M A Iñiguez & M Fresno

  3. Division of Physiological Chemistry II, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden

    H Hanaka & O Rådmark

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  1. S Donnini
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  2. F Finetti
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Correspondence to M Ziche.

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Donnini, S., Finetti, F., Terzuoli, E. et al. EGFR signaling upregulates expression of microsomal prostaglandin E synthase-1 in cancer cells leading to enhanced tumorigenicity. Oncogene 31, 3457–3466 (2012). https://doi.org/10.1038/onc.2011.503

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  • DOI: https://doi.org/10.1038/onc.2011.503

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