Telomerase a prognostic marker an therapeutic target

Malignant glioma is the most common and aggressive form of tumours and is usually refractory to therapy. Telomerase and its altered activity, distinguishing cancer cells, is an attractive molecular target in glioma therapeutics. The aim of this thesis was to silence telomerase at the genetic level with a view to highlight the changes caused in the cancer proteome and identify the potential downstream pathways controlled by telomerase in tumour progression and maintenance. A comprehensive proteomic study utilizing 2D-DIGE and MALDI-TOF were used to assess the effect of inhibiting two different regulatory mechanisms of telomerase in glioma. RNAi was used to target hTERT and Hsp90α. Inhibition of telomerase activity resulted in down regulation of various cytoskeletal proteins with correlative evidence of the involvement of telomerase in regulating the expression of vimentin. Vimentin plays an important role in tumour metastasis and is used as an indicator of glioma metastasis. Inhibition of telomerase via sihTERT results in the down regulation of vimentin expression in glioma cell lines in a grade specific manner. While, 9 of 12 glioblastoma tissues (grade IV) showed vimentin to be highly expressed, its expression was absent in lower grades and normal tissues. This suggests that vimentin can be potentially used as a glioma progressive marker. This is the first study to report the potential involvement of telomerase in the regulation of vimentin expression. This study also identified that combination therapy, comprising siRNA targeted towards telomerase regulatory mechanisms and the natural product Epigallocatechin-3-gallate (ECGC), results in decreased cell viability producing comparable results to that of other chemotherapeutic drugs.

Name dc:type.qualificationname

phd

Level dc:type.qualificationlevel

doctoral

Grantor dc:publisher.institution

University of Central Lancashire

Year dc:date.issued

2010

Author dc:creator

• Thakkar, Dipti S

• B110 - Anatomy

Statement dc:rights

• 1. Cruickshanks, N., Shervington, L., Patel, R., Munje, C., Thakkar, D., Shervington, A. Can hsp90alpha-Targeted siRNA Combined With TMZ Be a Future Therapy for Glioma? Cancer Invest. 2010. DOI: 10.3109/07357901003630967. 2. Shervington, A., Pawar, V., Menon, S., Thakkar, D., Patel, R. The sensitization of glioma cells to cisplatin and tamoxifen by the use of catechin. Mol. Biol. Rep. 2009;36(5):1181-1186. 3. Thakkar, D, Shervington, A. Proteomics: the tool to bridge the gap between the facts and fables of telomerase. Crit Rev Oncog. 2008;14(4):203-215. 4. Thakkar, D., Shervington, L., Shervington, A. Insight into glioma metastasis mechanism by regulation of vimentin via telomerase: the unnamed soldier identified by proteomic studies. Submitted to Cancer Investigations (accepted manuscript).

Language dc:language

en