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.
Highlights
Salivary gland cancer (SGC) is a relatively rare group of tumors, with annual incidence rates between 0.05 to 2 new cases per 100,000 [1]
We evaluated the response of three different mucoepidermoid carcinoma (MEC) cell lines, recently established at the University of Michigan School of Dentistry, [28, 29] using a wide range of ionizing radiation (IR) doses (0, 2, 4, 6 and 8 Gy)
Previous studies have shown that other carcinomas cells, such as cervical squamous cell carcinoma, have a much lower survival fraction at 2 Gy (SF2) (0.27 to 0.75) compared to our MEC cell lines [30]
Summary
Salivary gland cancer (SGC) is a relatively rare group of tumors, with annual incidence rates between 0.05 to 2 new cases per 100,000 [1]. In the US, the incidence of SGC significantly increased from 1974–1976 to 1998–1999 and accounted for 6.3% compared to 8.1% of all head and neck cancers, respectively [2]. More frequently in the lungs, is the primary cause of death and occurs slowly, with patients surviving up to 20 years [1]. Treatment for MEC derives from therapeutic protocols optimized for head and neck squamous cell carcinomas [7]. Postoperative radiotherapy is suitable for patients with high-grade tumors and advanced disease, positive margins and perineural or vascular invasion [1]. The low survival rates that occur in the long-term underscore the urgent need to identify molecular targets that sensitize SGC cells to radiotherapy
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