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

• Published in: Oncogene Vol. 31; no. 1; pp. 48 - 59
• Main Authors: Zaric, J, Joseph, J-M, Tercier, S, Sengstag, T, Ponsonnet, L, Delorenzi, M, Rüegg, C
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 05.01.2012; Nature Publishing Group
• Subjects: Actin; adherens junctions; Animals; Antitumor agents; Apoptosis; beta Catenin - physiology; catenin; Celecoxib; Cell Adhesion; Cell Adhesion Molecules, Neuronal - physiology; Cell Biology; Cell Line, Tumor; Cell migration; Cell Movement - drug effects; Cells; Colon cancer; Colorectal cancer; Colorectal Neoplasms - drug therapy; Colorectal Neoplasms - pathology; Cyclooxygenase 2 Inhibitors - pharmacology; Cyclooxygenase-2; Cyclooxygenases; Cytology; Drug therapy; E-Cadherin; Enzymes; Familial adenomatous polyposis; Female; Fibers; Human Genetics; Humans; Internal Medicine; Lung Neoplasms - secondary; matrix protein; Medicine; Medicine & Public Health; Metastases; Mice; Neoplasm Invasiveness; Nodules; Nonsteroidal antiinflammatory drugs; Oncology; original-article; Paracrine signalling; Physiological aspects; Prostaglandins; Proteins; Risk factors; Signal transduction; Stress; Tumor proteins; Tumor suppressor genes; Tumor Suppressor Proteins - physiology; Tumors; Wnt protein; Wnt Signaling Pathway; Switzerland; Japan; tumor suppressor; Wnt signaling; colorectal cancer; COX-2; metastasis
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2011.218

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.