The role of c-FLIP in regulating resistance to ionizing radiation
type: CreativeWork
description: Resistance to radiotherapy is a significant cause of treatment failure and tumour relapse. Therefore, strategies to improve the efficiency of cell death induction by ionizing radiation (IR) are required to improve therapeutic outcomes. FLIP, anendogenous caspase-8 inhibitor is a critical regulator of cell death that is frequently overexpressed in various cancers. FLIP overexpression in cancer contributes to resistance to death receptor- and chemotherapy- induced cell death. Thus, this Thesis investigated the role of FLIP in regulating resistance to IR. FLIP protein levels were down regulated by RNA interference or stably overexpressed by retroviral methods, and resulted in enhanced radio protection and radio resistance respectively. The effect of FLIP modulation on IR-induced cell death was assessed by caspase activity assays, short-term cell death and clonogenic survival assays. Overexpression of a FLIP mutant which cannot interact with its binding partner FADD, and thus cannot inhibit caspase-8 activation, did not protect cells from IR induced cell death, indicating that the FLIP-FADD protein-protein interaction and consequential inhibition of caspase-8 activity is mainly responsible for radio protection conferred by FLIP overexpression. This study provides convincing evidence indicating that FLIP should be investigated in clinical samples as a predictive biomarker of resistance to radiotherapy. Clinically approved HDAC inhibitors were used to down regulate FLIP protein levels, and the effect on IR-induced cell death was assessed. The results presented in this study reveal that F1DAC inhibitors sensitize non-small cell lung carcinoma (NSCLC) cell lines to IR. Furthermore, the radiosensitizing properties of HDAC inhibitors were highly dependent on their ability to suppress FLIP expression.Therefore. FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize and improve control of non-small cell lung carcinoma tumours, and the…
abstract: Resistance to radiotherapy is a significant cause of treatment failure and tumour relapse. Therefore, strategies to improve the efficiency of cell death induction by ionizing radiation (IR) are required to improve therapeutic outcomes. FLIP, anendogenous caspase-8 inhibitor is a critical regulator of cell death that is frequently overexpressed in various cancers. FLIP overexpression in cancer contributes to resistance to death receptor- and chemotherapy- induced cell death. Thus, this Thesis investigated the role of FLIP in regulating resistance to IR. FLIP protein levels were down regulated by RNA interference or stably overexpressed by retroviral methods, and resulted in enhanced radio protection and radio resistance respectively. The effect of FLIP modulation on IR-induced cell death was assessed by caspase activity assays, short-term cell death and clonogenic survival assays. Overexpression of a FLIP mutant which cannot interact with its binding partner FADD, and thus cannot inhibit caspase-8 activation, did not protect cells from IR induced cell death, indicating that the FLIP-FADD protein-protein interaction and consequential inhibition of caspase-8 activity is mainly responsible for radio protection conferred by FLIP overexpression. This study provides convincing evidence indicating that FLIP should be investigated in clinical samples as a predictive biomarker of resistance to radiotherapy. Clinically approved HDAC inhibitors were used to down regulate FLIP protein levels, and the effect on IR-induced cell death was assessed. The results presented in this study reveal that F1DAC inhibitors sensitize non-small cell lung carcinoma (NSCLC) cell lines to IR. Furthermore, the radiosensitizing properties of HDAC inhibitors were highly dependent on their ability to suppress FLIP expression.Therefore. FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radiosensitize and improve control of non-small cell lung carcinoma tumours, and the…
author: McLaughlin, Kylie Anne Jacqueline
language: eng
date published: 2016-7
date modified: 2026-07-24T03:55:05Z
provider: Queen's University Belfast
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Queen's University Belfast