Aslam, Mohammed Afeef
(2011)
An investigation of GRP78 expression and inhibition in squamous cell carcinoma of the head and neck.
PhD thesis, University of Liverpool.
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Abstract
GRP78 is a known cyto-protective gene which is induced in microenvironments typical of tumours with low glucose and hypoxia. Furthermore up-regulation of GRP78 has been linked to chemo- and radioresistance as well as poor survival outcome. This study is the first to confirm that GRP78 is up-regulated in tumours of the oropharynx, larynx and hypopharynx compared with matched histologically normal tissue (p(Χ2)<0.001). Up-regulation of GRP78 may be important for tumour development and therefore we have investigated the consequences of inhibition of GRP78 in cells derived from laryngeal squamous cell carcinomas (LSCC). EGF-SubA is a novel drug consisting of EGF covalently attached to the A subunit of an E.coli derived AB5 toxin which can cleave GRP78. EGF-SubA was able to induce EGFR-dependent cytotoxicity in a panel of seven laryngeal SCC cells with an IC50 range of between 4-100pM. EGF-SubA treatment induced G1 cell cycle arrest as well as apoptosis. Therefore apoptosis may be the mechanism by which EGF-SubA causes cell death. In vitro studies demonstrated that EGF-SubA enhances the effects of clinically relevant genotoxic agents. Two Gy survival fractions (SF2) were significantly reduced with EGF-SubA pre-treatment ... (continues)
Item Type: | Thesis (PhD) |
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Additional Information: | alt_title: Targeting of protein chaperones as novel therapies for head and neck cancer Date: 2011-08 (completed) |
Subjects: | ?? RC0254 ?? |
Divisions: | Faculty of Health and Life Sciences > Institute of Systems, Molecular and Integrative Biology |
Depositing User: | Symplectic Admin |
Date Deposited: | 23 May 2012 10:26 |
Last Modified: | 29 Oct 2024 18:07 |
DOI: | 10.17638/00003813 |
Supervisors: |
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URI: | https://livrepository.liverpool.ac.uk/id/eprint/3813 |