E-Thesis 112 views
Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2 / BENJAMIN SKALKOYANNIS
Swansea University Author: BENJAMIN SKALKOYANNIS
DOI (Published version): 10.23889/SUthesis.59225
Abstract
Background: Pancreatic cancer is one of the deadliest cancers. The cell surface expressing the interleukin-13 receptor (IL13R)α2, which is overexpressed in tumours such as pancreatic cancer, contains four N-glycosylation sites (N115, N215, N290 and N299) and the conserved regions such as the WSXWS a...
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Swansea
2022
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| Institution: | Swansea University |
| Degree level: | Doctoral |
| Degree name: | Ph.D |
| Supervisor: | Kanamarlapudi, Venkateswarlu |
| URI: | https://cronfa.swan.ac.uk/Record/cronfa59225 |
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| Abstract: |
Background: Pancreatic cancer is one of the deadliest cancers. The cell surface expressing the interleukin-13 receptor (IL13R)α2, which is overexpressed in tumours such as pancreatic cancer, contains four N-glycosylation sites (N115, N215, N290 and N299) and the conserved regions such as the WSXWS and dileucine motifs. Recently, a peptide specifically binding to IL13Rα2 has been identified and termed Pep1. The overall objective of this study is to assess the drug targetability of IL13Rα2 in pancreatic cancer and the importance of N-glycosylation and the other conserved motifs of the receptor for its structure and function. Hypothesis and aims: We hypothesised that Pep1, coupled with a lytic peptide such as Phor21, could target and kill pancreatic cancer cells expressing IL13Rα2 and that the N-glycosylation is important for the structure and function of the receptor. This was tested by investigating the expression of IL13Rα2 in pancreatic cancer cell lines and tissues and the sensitivity to Pep1-Phor21 (aim 1), exploring the importance of the N-glycosylation and the other conserved sites in trafficking and the ligand binding of IL13Rα2 (aim 2), and identifying a new peptide by screening a phage display dodecamer peptide library that potential bind IL13Rα2 (aim 3). Results: IL13Rα2 was seen highly expressed in many pancreatic cancer cell lines and tissues but not in a non-tumour cell line or tissues. Treatment with Pep1-Phor21 in vitro reduced viability of IL13Rα2+ve pancreatic cancer cells, while leaving IL13Rα2-ve cells unaffected. Using mutational analysis, the N-glycosylation and the WSXWS motif of the receptor were shown to be important for IL13Rα2 trafficking to the cell membrane and its binding to IL13. Using a phage display dodecamer peptide library screening for the IL13Rα2 binding, seven peptides were isolated. Conclusion: IL13Rα2 is expressed in pancreatic cancer cell lines and Pep1-Phor21 can successfully elicit killing in IL13Rα2+ve cells. The N-glycosylation of IL13Rα2 is important for cell surface expression of the receptor, while the N-glycosylation and WSXWS motif of IL13Rα2 are important for the ligand binding and structure of the receptor, respectively. The phage display peptide library screening did not yield a novel IL13Rα2 binding peptide. |
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| Item Description: |
A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions. |
| Keywords: |
IL13Rα2; N-glycosylation, IL13, pancreatic cancer |
| College: |
Faculty of Medicine, Health and Life Sciences |