Overcoming adaptive resistance in mucoepidermoid carcinoma through inhibition of the IKK-β/IκBα/NFκB axis

// Vivian P. Wagner 1, 2, 3 , Marco A.T. Martins 1, 2 , Manoela D. Martins 1, 2, 3 , Kristy A. Warner 4 , Liana P. Webber 1, 2, 3 , Cristiane H. Squarize 1, 5 , Jacques E. Nör 4, 5, 6, 7 , Rogerio M. Castilho 1, 5 1 Laboratory of Epithelial Biology, Department of Periodontics and Oral Medicine, University of Michigan School of Dentistry, Ann Arbor, MI, USA 2 Experimental Pathology Unit, Clinics Hospital of Porto Alegre, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 3 Department of Oral Pathology, School of Dentistry, Federal University of Rio Grande do Sul, Porto Alegre, RS, Brazil 4 Department of Restorative Sciences, University of Michigan School of Dentistry, Ann Arbor, MI, USA 5 Comprehensive Cancer Center, University of Michigan Ann Arbor, MI, USA 6 Department of Otolaryngology, Medical School, University of Michigan, Ann Arbor, MI, USA 7 Department of Biomedical Engineering, University of Michigan College of Engineering, Ann Arbor, MI, USA Correspondence to: Rogerio M. Castilho, email: rcastilh@umich.edu Keywords: salivary cancer, irradiation, IKKα, cancer stem cells, radio-adaptive Received: May 03, 2016 Accepted: September 15, 2016 Published: September 22, 2016 ABSTRACT Patients with mucoepidermoid carcinoma (MEC) experience low survival rates and high morbidity following treatment, yet the intrinsic resistance of MEC cells to ionizing radiation (IR) and the mechanisms underlying acquired resistance remain unexplored. Herein, we demonstrated that low doses of IR intrinsically activated NFκB in resistant MEC cell lines. Moreover, resistance was significantly enhanced in IR-sensitive cell lines when NFκB pathway was stimulated. Pharmacological inhibition of the IKK-β/IκBα/NFκB axis, using a single dose of FDA-approved Emetine, led to a striking sensitization of MEC cells to IR and a reduction in cancer stem cells. We achieved a major step towards better understanding the basic mechanisms involved in IR-adaptive resistance in MEC cell lines and how to efficiently overcome this critical problem.