An investigation of GRP78 expression and inhibition in squamous cell carcinoma of the head and neck


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)
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:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3813
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