FLIP: a targetable mediator of resistance to radiation in non-small cell lung cancer

McLaughlin, Kylie and Nemeth, Zsuzsanna and Bradley, Conor and Humphreys, Luke and Stasik, Izabela and Fenning, Catherine and Majkut, Joanna and Higgins, Catherine and Crawford, Nyree and Holohan, Caitriona and Johnston, Patrick and Harrison, Timothy and Hanna, Gerard and Butterworth, Karl and Prise, Kevin and Longley, Daniel (2016) FLIP: a targetable mediator of resistance to radiation in non-small cell lung cancer. Molecular Cancer Therapeutics. ISSN 1538-8514

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Abstract

Resistance to radiotherapy due to insufficient cancer cell death is a significant cause of treatment failure in non-small cell lung cancer (NSCLC). The endogenous caspase-8 inhibitor, FLIP, is a critical regulator of cell death that is frequently overexpressed in NSCLC and is an established inhibitor of apoptotic cell death induced via the extrinsic death receptor pathway. Apoptosis induced by ionizing radiation (IR) has been considered to be mediated predominantly via the intrinsic apoptotic pathway; however, we found that IR-induced apoptosis was significantly attenuated in NSCLC cells when caspase-8 was depleted using RNA interference (RNAi), suggesting involvement of the extrinsic apoptosis pathway. Moreover, overexpression of wild-type FLIP, but not a mutant form that cannot bind the critical death receptor adaptor protein FADD, also attenuated IR-induced apoptosis, confirming the importance of the extrinsic apoptotic pathway as a determinant of response to IR in NSCLC. Importantly, when FLIP protein levels were down-regulated by RNAi, IR-induced cell death was significantly enhanced. The clinically relevant histone deacetylase (HDAC) inhibitors vorinostat and entinostat were subsequently found to sensitize a subset of NSCLC cell lines to IR in a manner that was dependent on their ability to suppress FLIP expression and promote activation of caspase-8. Entinostat also enhanced the anti-tumor activity of IR in vivo. Therefore, FLIP down-regulation induced by HDAC inhibitors is a potential clinical strategy to radio-sensitize NSCLC and thereby improve response to radiotherapy. Overall, this study provides the first evidence that pharmacological inhibition of FLIP may improve response of NCSLC to IR.

Item Type: Article
Keywords: Non-small cell lung cancer, FLIP, caspase-8, ionizing radiation, HDAC inhibitor
Faculty / Department: Faculty of Science > School of Health Sciences
Depositing User: Izabela Stasik
Date Deposited: 09 Aug 2016 13:24
Last Modified: 31 Jul 2017 00:15
URI: http://hira.hope.ac.uk/id/eprint/1606

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