Our earlier studies indicated that ionizing radiation (IR) induces NF-κB-dependent clonal expansion of therapy resistant tumor cells. Herein, we investigated whether mitigation of NF-κB-dependent telomerase activation by EGFR tyrosine kinase inhibitor can enhance IR-induced celling killing. SCC-4 and SCC-9 cells exposed to IR with or without Pelitinib were examined for NF-κB and hTERT transcription using luciferase reporter assays. NF-κB-dependent hTERT transcription was confirmed by either muting NF-κB or by using hTERT constructs lacking NF-κB binding sites. hTERT, mRNA, telomerase activity and cell survival of tumor cells were analyzed using QPCR, TRAP and clonogenic assay, respectively. Pelitinib inhibited IR-induced NF-κB, telomerase activity and hTERT transactivation. Ionizing radiation-induced telomerase activity is regulated at the transcriptional level by triggering TERT promoter activation. Functional NF-κB mediates telomerase activity by binding to the κB binding region in the promoter region of TERT. Elimination of the NF-κB recognition site on telomerase or muting NF-κB compromises IR-induced telomerase promoter activation. We found that Pelitinib inhibited IR-induced TERT transcription, transactivation and telomerase activation in IR-exposed and NF-κB-overexpressed cells. Furthermore, Pelitinib potentiates IR-induced cell killing. Our results strongly suggest that IR-induced NF-κB-mediated cell survival is supported by telomerase activation. We propose that if this pathway can be inhibited with Pelitinib treatment, one could further enhance therapeutic outcome in squamous cell carcinoma.
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Vol. 179 • No. 3