Use this URL to cite or link to this record in EThOS: http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680869
Title: Inhibition of treatment-induced cell survival signalling enhances radiosensitivity of PTEN-deficient prostate cancer
Author: Armstrong, Chris
ISNI:       0000 0004 5917 4486
Awarding Body: Queen's University Belfast
Current Institution: Queen's University Belfast
Date of Award: 2015
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Abstract:
Loss of the tumour suppressor PTEN is a common feature of prostate cancer (PCa) and has recently been identified as a prognostic factor for patient relapse following radiotherapy. Published studies in our laboratory have identified CXCL8 signalling as a mediator of PTEN-depleted disease progression and therapeutic resistance. Therefore, experiments were designed to determine whether ionising radiation (IR) could selectively induce CXCL8 signalling in PTEN-deficient cells. Furthermore, we aimed to determine whether therapeutic targeting of the CXCL8 pathway could enhance PCa cell radiosensitivity. The results in this thesis show how exposure to IR increased gene and protein expression of CXCL8. In addition, inhibiting CXCL8 signalling with receptor-targeted siRNA or peptides increased PTEN-depleted cell sensitivity to IR. In vivo, treatment of PTEN-deficient xenografts with IR and a CXCR1/2-targeted pepducin (x1/2pal-i3) resulted in significant tumour growth delay. Subsequent analysis of tumour material confirmed that this was mediated by modulation of IR-induced anti-apoptotic proteins. Similar to CXCL8 signalling, macrophage infiltration has been associated with enhanced disease progression and poor therapeutic outcomes in prostate cancer patients. Unpublished data in our . laboratory has shown that loss of PTEN can predict for macrophage infiltration in prostate patient samples. Experiments were therefore designed to determine the impact of IR on macrophage-mediated paracrine signalling. Using the THP-1 cell line to model the macrophage component, co-culture systems demonstrated that the presence of microenvironment cells can enhance prostate cancer cell radioresistance. Furthermore, IR was shown to induce secretion of the cytokine TNF-α and this was sufficient to initiate NFKB-mediated upregulation of anti-apoptotic protein expression. Inhibition of cellular inhibitor of apoptosis protein-1 (clAP-1) by Smac-mimetics overcame TNF-α pro-survival effects and reduced cell viability by 50%. In addition, pre-treatment with Smac-mimetics sensitised DU145 cells to ionising radiation following macrophage co-culture.
Supervisor: Not available Sponsor: Not available
Qualification Name: Thesis (Ph.D.) Qualification Level: Doctoral
EThOS ID: uk.bl.ethos.680869  DOI: Not available
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