title: EGFR tyrosine kinase inhibitor pelitinib regulates radiation-induced p65-dependent telomerase activation in squamous cell carcinoma.
abstract: 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.
authors: Departments of a Radiation Oncology, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA. naravind@ouhsc.edu
authors: Natarajan
authors: N
authors: Aravindan
authors: Sheeja
authors: S
authors: Aravindan
authors: Terence S
authors: TS
authors: Herman
authors: Mohan
authors: M
authors: Natarajan
mesh_terms: D000634:Aminoquinolines / Q000494:pharmacology*; D000814:Aniline Compounds / Q000494:pharmacology*; D002294:Carcinoma, Squamous Cell / Q000201:enzymology* / Q000473:pathology; D004789:Enzyme Activation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors*; D006801:Humans; D016328:NF-kappa B / Q000378:metabolism; D016133:Polymerase Chain Reaction; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D019098:Telomerase / Q000378:metabolism*
chemical_list: D000634:Aminoquinolines; D000814:Aniline Compounds; D016328:NF-kappa B; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors; D019098:Telomerase; C413879:EKB 569