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Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells

Oncogene volume 31, pages 48–59 (2012)Cite this article

Abstract

Cyclooxyganase-2 (COX-2), a rate-limiting enzyme in the prostaglandin synthesis pathway, is overexpressed in many cancers and contributes to cancer progression through tumor cell-autonomous and paracrine effects. Regular use of non-steroidal anti-inflammatory drugs or selective COX-2 inhibitors (COXIBs) reduces the risk of cancer development and progression, in particular of the colon. The COXIB celecoxib is approved for adjunct therapy in patients with Familial adenomatous polyposis at high risk for colorectal cancer (CRC) formation. Long-term use of COXIBs, however, is associated with potentially severe cardiovascular complications, which hampers their broader use as preventive anticancer agents. In an effort to better understand the tumor-suppressive mechanisms of COXIBs, we identified MAGUK with Inverted domain structure-1 (MAGI1), a scaffolding protein implicated in the stabilization of adherens junctions, as a gene upregulated by COXIB in CRC cells and acting as tumor suppressor. Overexpression of MAGI1 in CRC cell lines SW480 and HCT116 induced an epithelial-like morphology; stabilized E-cadherin and β-catenin localization at cell–cell junctions; enhanced actin stress fiber and focal adhesion formation; increased cell adhesion to matrix proteins and suppressed Wnt signaling, anchorage-independent growth, migration and invasion in vitro. Conversely, MAGI1 silencing decreased E-cadherin and β-catenin localization at cell–cell junctions; disrupted actin stress fiber and focal adhesion formation; and enhanced Wnt signaling, anchorage-independent growth, migration and invasion in vitro. MAGI1 overexpression suppressed SW480 and HCT116 subcutaneous primary tumor growth, attenuated primary tumor growth and spontaneous lung metastasis in an orthotopic model of CRC, and decreased the number and size of metastatic nodules in an experimental model of lung metastasis. Collectively, these results identify MAG1 as a COXIB-induced inhibitor of the Wnt/β-catenin signaling pathway, with tumor-suppressive and anti-metastatic activity in experimental colon cancer.

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Acknowledgements

We thank Drs M Aguet, Y Hata, L Naldini, A Follenzi and R Iggo for sharing reagents; F Derouet and D Uldry for invaluable technical assistance; N Rives for proof reading the paper and Pfizer for providing celecoxib. This work was supported by grants from the Medic Foundation, the National Center for Competence in Research (NCCR, Molecular Oncology, a research instrument of the Swiss National Science Foundation), the European Union under the auspices of the FP7 collaborative project TuMIC (contract number HEALTH-F2-2008-201662) and by the Swiss Cancer League (OCS 020020-02-2007).

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  1. T Sengstag

    Present address: 6Current address: OSC—Omics Science Center, RIKEN Yokohama Institute, 1-7-22 Suehirocho, Tsurumiku, Yokohama 230-0045, Japan,

Authors and Affiliations

  1. Division of Experimental Oncology, Multidisciplinary Oncology Center (CePO), University Medical Center (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland

    J Zaric, L Ponsonnet & C Rüegg

  2. Department of Medicine, Pathology, Faculty of Science, University of Fribourg (UNIFR), Fribourg, Switzerland

    J Zaric, L Ponsonnet & C Rüegg

  3. National Center for Competence in Research (NCCR), Molecular Oncology, Swiss Institute for Experimental Cancer Research (ISREC)-Ecole Polytechnique Fédérale de Lausanne (EPFL), Lausanne, Switzerland

    J Zaric, M Delorenzi & C Rüegg

  4. Department of Pediatric Surgery, University Medical Center (CHUV), University of Lausanne (UNIL), Lausanne, Switzerland

    J-M Joseph & S Tercier

  5. Swiss Institute of Bioinformatics (SIB), Lausanne, Switzerland

    T Sengstag & M Delorenzi

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Zaric, J., Joseph, JM., Tercier, S. et al. Identification of MAGI1 as a tumor-suppressor protein induced by cyclooxygenase-2 inhibitors in colorectal cancer cells. Oncogene 31, 48–59 (2012). https://doi.org/10.1038/onc.2011.218

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  • DOI: https://doi.org/10.1038/onc.2011.218

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