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The role of E-cadherin in colon cancer drug resistance

Murray, Lynn (2010) The role of E-cadherin in colon cancer drug resistance. PhD thesis, University of Glasgow.

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Abstract

As resistance to current therapies remains one of the major hurdles to the successful treatment of advanced colorectal cancer, we need to understand the mechanisms by which cancer cells evade therapy-induced cell death. I have investigated whether there is a link between epithelial cell adhesions, and acquired resistance to 5-fluorouracil (5-FU). I compared three pairs of human colorectal 5-FU-sensitive and -resistant cell lines, and investigated whether there was a direct role for E-cadherin and/or the Src family kinase, c- Yes (which is co-amplified with thymidylate synthase) in promoting resistance to 5-FU. I found that while knockdown of c-Yes expression had no effect, disruption of E-cadherin using a blocking antibody caused a reduction in colon cancer cell proliferation and some re-sensitisation to 5-FU. The resistant cells displayed intrinsically higher activities of putative survival pathways, namely the PI3-kinase/Akt and the MEK/MAP kinase pathways, and these were suppressed when E-cadherin function was blocked. Furthermore, the resistant cells displayed a greater dependence on signalling via the PI3- kinase/Akt pathway for their survival. Finally, preliminary experiments established a possible link between the integrity of E-cadherin-mediated cell-cell junctions, signalling through the PI3-kinase/Akt pathway and nuclear localisation of the apoptotic regulatory tumour suppressor protein p53 in modulation of 5-FU-resistance.

Item Type: Thesis (PhD)
Qualification Level: Doctoral
Keywords: Colon, cancer, E-cadherin
Subjects: R Medicine > RC Internal medicine > RC0254 Neoplasms. Tumors. Oncology (including Cancer)
R Medicine > RM Therapeutics. Pharmacology
Colleges/Schools: College of Medical Veterinary and Life Sciences > Institute of Cancer Sciences
Supervisor's Name: Frame, Prof. Margaret
Date of Award: 2010
Depositing User: MISS LYNN MURRAY
Unique ID: glathesis:2010-1943
Copyright: Copyright of this thesis is held by the author.
Date Deposited: 16 Jun 2010
Last Modified: 10 Dec 2012 13:48
URI: http://theses.gla.ac.uk/id/eprint/1943

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