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Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2 / BENJAMIN SKALKOYANNIS

Swansea University Author: BENJAMIN SKALKOYANNIS

  • Redacted version - open access under embargo until: 20th January 2027

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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Published: Swansea 2022
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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first_indexed 2022-01-21T10:32:17Z
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fullrecord <?xml version="1.0"?><rfc1807><datestamp>2022-01-21T10:56:06.3526929</datestamp><bib-version>v2</bib-version><id>59225</id><entry>2022-01-21</entry><title>Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2</title><swanseaauthors><author><sid>639567b35b50439e3d6eb3ecf7c2bd50</sid><firstname>BENJAMIN</firstname><surname>SKALKOYANNIS</surname><name>BENJAMIN SKALKOYANNIS</name><active>true</active><ethesisStudent>false</ethesisStudent></author></swanseaauthors><date>2022-01-21</date><abstract>Background: Pancreatic cancer is one of the deadliest cancers. The cell surface expressing the interleukin-13 receptor (IL13R)&#x3B1;2, 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 IL13R&#x3B1;2 has been identified and termed Pep1. The overall objective of this study is to assess the drug targetability of IL13R&#x3B1;2 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 IL13R&#x3B1;2 and that the N-glycosylation is important for the structure and function of the receptor. This was tested by investigating the expression of IL13R&#x3B1;2 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 IL13R&#x3B1;2 (aim 2), and identifying a new peptide by screening a phage display dodecamer peptide library that potential bind IL13R&#x3B1;2 (aim 3). Results: IL13R&#x3B1;2 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 IL13R&#x3B1;2+ve pancreatic cancer cells, while leaving IL13R&#x3B1;2-ve cells unaffected. Using mutational analysis, the N-glycosylation and the WSXWS motif of the receptor were shown to be important for IL13R&#x3B1;2 trafficking to the cell membrane and its binding to IL13. Using a phage display dodecamer peptide library screening for the IL13R&#x3B1;2 binding, seven peptides were isolated. Conclusion: IL13R&#x3B1;2 is expressed in pancreatic cancer cell lines and Pep1-Phor21 can successfully elicit killing in IL13R&#x3B1;2+ve cells. The N-glycosylation of IL13R&#x3B1;2 is important for cell surface expression of the receptor, while the N-glycosylation and WSXWS motif of IL13R&#x3B1;2 are important for the ligand binding and structure of the receptor, respectively. The phage display peptide library screening did not yield a novel IL13R&#x3B1;2 binding peptide.</abstract><type>E-Thesis</type><journal/><volume/><journalNumber/><paginationStart/><paginationEnd/><publisher/><placeOfPublication>Swansea</placeOfPublication><isbnPrint/><isbnElectronic/><issnPrint/><issnElectronic/><keywords>IL13R&#x3B1;2; N-glycosylation, IL13, pancreatic cancer</keywords><publishedDay>21</publishedDay><publishedMonth>1</publishedMonth><publishedYear>2022</publishedYear><publishedDate>2022-01-21</publishedDate><doi>10.23889/SUthesis.59225</doi><url/><notes>A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions.</notes><college>COLLEGE NANME</college><CollegeCode>COLLEGE CODE</CollegeCode><institution>Swansea University</institution><supervisor>Kanamarlapudi, Venkateswarlu</supervisor><degreelevel>Doctoral</degreelevel><degreename>Ph.D</degreename><degreesponsorsfunders>Life Sciences Research Network Wales</degreesponsorsfunders><apcterm/><lastEdited>2022-01-21T10:56:06.3526929</lastEdited><Created>2022-01-21T09:50:50.9286378</Created><path><level id="1">Faculty of Medicine, Health and Life Sciences</level><level id="2">Swansea University Medical School - Medicine</level></path><authors><author><firstname>BENJAMIN</firstname><surname>SKALKOYANNIS</surname><order>1</order></author></authors><documents><document><filename>Under embargo</filename><originalFilename>Under embargo</originalFilename><uploaded>2022-01-21T10:49:51.6070732</uploaded><type>Output</type><contentLength>6749886</contentLength><contentType>application/pdf</contentType><version>Redacted version - open access</version><cronfaStatus>true</cronfaStatus><embargoDate>2027-01-20T00:00:00.0000000</embargoDate><documentNotes>Copyright: The author, Benjamin Skalkoyannis, 2022.</documentNotes><copyrightCorrect>true</copyrightCorrect><language>eng</language></document></documents><OutputDurs/></rfc1807>
spelling 2022-01-21T10:56:06.3526929 v2 59225 2022-01-21 Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2 639567b35b50439e3d6eb3ecf7c2bd50 BENJAMIN SKALKOYANNIS BENJAMIN SKALKOYANNIS true false 2022-01-21 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. E-Thesis Swansea IL13Rα2; N-glycosylation, IL13, pancreatic cancer 21 1 2022 2022-01-21 10.23889/SUthesis.59225 A selection of third party content is redacted or is partially redacted from this thesis due to copyright restrictions. COLLEGE NANME COLLEGE CODE Swansea University Kanamarlapudi, Venkateswarlu Doctoral Ph.D Life Sciences Research Network Wales 2022-01-21T10:56:06.3526929 2022-01-21T09:50:50.9286378 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine BENJAMIN SKALKOYANNIS 1 Under embargo Under embargo 2022-01-21T10:49:51.6070732 Output 6749886 application/pdf Redacted version - open access true 2027-01-20T00:00:00.0000000 Copyright: The author, Benjamin Skalkoyannis, 2022. true eng
title Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
spellingShingle Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
BENJAMIN SKALKOYANNIS
title_short Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
title_full Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
title_fullStr Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
title_full_unstemmed Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
title_sort Studying the therapeutic potential and N-glycosylation of interleukin 13 receptor alpha 2
author_id_str_mv 639567b35b50439e3d6eb3ecf7c2bd50
author_id_fullname_str_mv 639567b35b50439e3d6eb3ecf7c2bd50_***_BENJAMIN SKALKOYANNIS
author BENJAMIN SKALKOYANNIS
author2 BENJAMIN SKALKOYANNIS
format E-Thesis
publishDate 2022
institution Swansea University
doi_str_mv 10.23889/SUthesis.59225
college_str Faculty of Medicine, Health and Life Sciences
hierarchytype
hierarchy_top_id facultyofmedicinehealthandlifesciences
hierarchy_top_title Faculty of Medicine, Health and Life Sciences
hierarchy_parent_id facultyofmedicinehealthandlifesciences
hierarchy_parent_title Faculty of Medicine, Health and Life Sciences
department_str Swansea University Medical School - Medicine{{{_:::_}}}Faculty of Medicine, Health and Life Sciences{{{_:::_}}}Swansea University Medical School - Medicine
document_store_str 0
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description 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.
published_date 2022-01-21T04:16:22Z
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score 11.017776

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