Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.709545
Title: The role of c-Flip in regulating resistance to ionizing radiation
Author: McLaughlin, Kylie Anne Jacqueline
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2016
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Abstract:
Resistance to radiotherapy is a significant cause of treatment failure and tumour relapse. Strategies to improve the efficacy of radiotherapy are sought to improve therapeutic responses. c-FLIP is a critical regulator of the extrinsic apoptotic pathway and is frequently overexpressed in many cancers, including non-small cell lung carcinoma (NSCLC). c-FLIP overexpression contributes to resistance to death receptor- and chemotherapy-induced cell death through inhibition of caspase-8 activation. This Thesis demonstrates for the first time that c-FLIP is a critical regulator of ionizing radiation (IR)-induced cell death in in vitro models of NSCLC. Importantly, down-regulation of c-FLIP using siRNA sensitizes cells to IR, conversely, overexpression of c-FLIP confers increased radioresistance to cells. Overexpression of a c-FLIP-mutant which cannot interact with FADD and thereby cannot prevent caspase-8 activation does not protect cells from IR-induced cell death. Furthermore, silencing of caspase-8 or death receptors, particularly DR5 and TNFR1, attenuates IR-induced cell death indicating the importance of the extrinsic apoptotic pathway in mediating cellular responses to IR. c-FLIP depletion was also shown to increase levels of DNA damage, and further enhance IR-induced DNA damage. Given the increased radioresistance of c-FLIP overexpressing cells, c-FLIP expression should be investigated in clinical samples as a candidate predictive biomarker of response to radiotherapy. A FDA-approved HDAC inhibitor was used to downregulate c-FLIP protein levels and radiosensitize NSCLC cells. The radiosensitization was shown to be highly dependent on c-FLIP downregulation. Therefore, this study provides pre-clinical evidence that pharmacological inhibition of c-FLIP may improve the response of NSCLC to radiotherapy and enable improved control of radiation-resistant subpopulations of tumour cells that express high levels of c-FLIP.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.709545  DOI: Not available
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