The role of E-cadherin in colon cancer drug resistance

RC0254 Neoplasms. Tumors. Oncology (including Cancer);RM Therapeutics. Pharmacology

Murray, Lynn ; Frame, Margaret

University:University of Glasgow

Department:Institute of Cancer Sciences

关键词: Colon, cancer, E-cadherin;   

Others  :  http://theses.gla.ac.uk/1943/1/2010MurrayPhD.pdf

来源: University of Glasgow

【 摘 要 】

As resistance to current therapies remains one of the major hurdles to the successfultreatment of advanced colorectal cancer, we need to understand the mechanisms by whichcancer cells evade therapy-induced cell death. I have investigated whether there is a linkbetween epithelial cell adhesions, and acquired resistance to 5-fluorouracil (5-FU). Icompared three pairs of human colorectal 5-FU-sensitive and -resistant cell lines, andinvestigated 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. Ifound that while knockdown of c-Yes expression had no effect, disruption of E-cadherinusing a blocking antibody caused a reduction in colon cancer cell proliferation and somere-sensitisation to 5-FU. The resistant cells displayed intrinsically higher activities ofputative survival pathways, namely the PI3-kinase/Akt and the MEK/MAP kinasepathways, 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 apossible link between the integrity of E-cadherin-mediated cell-cell junctions, signallingthrough the PI3-kinase/Akt pathway and nuclear localisation of the apoptotic regulatorytumour suppressor protein p53 in modulation of 5-FU-resistance.