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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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
Funder's Name: UNSPECIFIED
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

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