The addition of celecoxib improves the antitumor effect of cetuximab in colorectal cancer: role of EGFR-RAS-FOXM1-β-catenin signaling axis
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Araceli Valverde1, Jon Peñarando1,2, Amanda Cañas1, Laura M. López-Sánchez1,2, Francisco Conde1,2, Silvia Guil-Luna1, Vanessa Hernández1,2, Carlos Villar3, Cristina Morales-Estévez1,4, Juan de la Haba-Rodríguez1,2,4, Enrique Aranda1,2,4, Antonio Rodríguez-Ariza1,2,4
1Instituto Maimónides de Investigación Biomédica de Córdoba (IMIBIC), Córdoba, Spain
2Centro de Investigacion Biomédica en Red de Cáncer, Madrid, Spain
3Unidad de Gestión Clínica de Anatomía Patológica, Hospital Universitario Reina Sofía, Córdoba, Spain
4Unidad de Gestión Clínica de Oncología, Hospital Universitario Reina Sofía, Córdoba, Spain
Antonio Rodríguez-Ariza, email: [email protected]
Keywords: β-catenin, colorectal cancer, COX-2, EGFR, FOXM1
Received: July 20, 2016 Accepted: January 23, 2017 Published: February 21, 2017
Here we showed that the addition of the COX-2 inhibitor celecoxib improved the antitumor efficacy in colorectal cancer (CRC) of the monoclonal anti-EGFR antibody cetuximab. The addition of celecoxib augmented the efficacy of cetuximab to inhibit cell proliferation and to induce apoptosis in CRC cells. Moreover, the combination of celecoxib and cetuximab was more effective than either treatment alone in reducing the tumor volume in a mouse xenograft model. The combined treatment enhanced the inhibition of EGFR signaling and altered the subcellular distribution of β-catenin. Moreover, knockdown of FOXM1 showed that this transcription factor participates in this enhanced antitumoral response. Besides, the combined treatment decreased β-catenin/FOXM1 interaction and reduced the cancer stem cell subpopulation in CRC cells, as indicated their diminished capacity to form colonospheres. Notably, the inmunodetection of FOXM1 in the nuclei of tumor cells in human colorectal adenocarcinomas was significantly associated with response of patients to cetuximab. In summary, our study shows that the addition of celecoxib enhances the antitumor efficacy of cetuximab in CRC due to impairment of EGFR-RAS-FOXM1-β-catenin signaling axis. Results also support that FOXM1 could be a predictive marker of response of mCRC patients to cetuximab therapy.
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