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Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide

Riaz Jannoo, William Walker, Venkat Kanamarlapudi Orcid Logo

Cancers, Volume: 15, Issue: 10, Start page: 2772

Swansea University Author: Venkat Kanamarlapudi Orcid Logo

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DOI (Published version): 10.3390/cancers15102772

Abstract

Highly metastatic breast cancers, such as triple-negative subtypes (TNBC), require the most effective treatments. Since interleukin-13 receptor (IL-13R)α2 is reportedly over-expressed in some cancers, we investigated here its expression and the feasibility of therapeutically targeting this receptor...

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Published in: Cancers
ISSN: 2072-6694
Published: MDPI AG 2023
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URI: https://cronfa.swan.ac.uk/Record/cronfa63511
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spelling v2 63511 2023-05-19 Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide 63741801137148abfa4c00cd547dcdfa 0000-0002-8739-1483 Venkat Kanamarlapudi Venkat Kanamarlapudi true false 2023-05-19 BMS Highly metastatic breast cancers, such as triple-negative subtypes (TNBC), require the most effective treatments. Since interleukin-13 receptor (IL-13R)α2 is reportedly over-expressed in some cancers, we investigated here its expression and the feasibility of therapeutically targeting this receptor in breast cancer using a novel hybrid cytolytic peptide (Pep-1-Phor21) consisting of IL-13Rα2-binding (Pep-1) and cytolytic (Phor21) domains. This study demonstrates that particularly TNBC tissues and cells display the prominent expression of IL-13Rα2. Furthermore, Pep-1-Phor21 induced the rapid necrosis of tumor cells expressing cell-surface IL-13Rα2. Notably, IL-13Rα2 expression was found to be epigenetically regulated in breast cancer cells in that the inhibition of histone deacetylase (HDAC) or DNA methyltransferase (DNMT) upregulated IL-13Rα2 expression, thereby sensitizing them to Pep-1-Phor21. IL-13Rα2-negative non-malignant cells were refractory to these epigenetic effects. Consistent with its cytolytic activity, Pep-1-Phor21 readily destroyed IL-13Rα2-expressing breast cancer spheroids with HDAC or DNMT inhibition, further enhancing cytolytic activity. Therefore, the Pep-1-Phor21-mediated targeting of IL-13Rα2 is a potentially novel therapeutic strategy for TNBC. Given that tumor cells can be selectively sensitized to Pep-1-Phor21 via the epigenetic up-regulation of IL-13Rα2, a combined adjuvant approach involving Pep-1-Phor21 and epigenetic inhibitors may be an effective strategy. Journal Article Cancers 15 10 2772 MDPI AG 2072-6694 IL-13Rα2; TNBC; cytolytic peptide; cytotoxic; adjuvant; epigenetic; cancer therapy 16 5 2023 2023-05-16 10.3390/cancers15102772 http://dx.doi.org/10.3390/cancers15102772 COLLEGE NANME Biomedical Sciences COLLEGE CODE BMS Swansea University 2024-01-08T13:42:30.9687948 2023-05-19T13:29:08.3395440 Faculty of Medicine, Health and Life Sciences Swansea University Medical School - Medicine Riaz Jannoo 1 William Walker 2 Venkat Kanamarlapudi 0000-0002-8739-1483 3 63511__27842__53208fede8064fa98337de2a8a058e58.pdf 63511.pdf 2023-06-13T15:37:11.6565003 Output 3088160 application/pdf Version of Record true © 2023 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). true eng https://creativecommons.org/licenses/by/4.0
title Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
spellingShingle Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
Venkat Kanamarlapudi
title_short Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
title_full Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
title_fullStr Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
title_full_unstemmed Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
title_sort Targeting and Sensitization of Breast Cancer Cells to Killing with a Novel Interleukin-13 Receptor α2-Specific Hybrid Cytolytic Peptide
author_id_str_mv 63741801137148abfa4c00cd547dcdfa
author_id_fullname_str_mv 63741801137148abfa4c00cd547dcdfa_***_Venkat Kanamarlapudi
author Venkat Kanamarlapudi
author2 Riaz Jannoo
William Walker
Venkat Kanamarlapudi
format Journal article
container_title Cancers
container_volume 15
container_issue 10
container_start_page 2772
publishDate 2023
institution Swansea University
issn 2072-6694
doi_str_mv 10.3390/cancers15102772
publisher MDPI AG
college_str Faculty of Medicine, Health and Life Sciences
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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
url http://dx.doi.org/10.3390/cancers15102772
document_store_str 1
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description Highly metastatic breast cancers, such as triple-negative subtypes (TNBC), require the most effective treatments. Since interleukin-13 receptor (IL-13R)α2 is reportedly over-expressed in some cancers, we investigated here its expression and the feasibility of therapeutically targeting this receptor in breast cancer using a novel hybrid cytolytic peptide (Pep-1-Phor21) consisting of IL-13Rα2-binding (Pep-1) and cytolytic (Phor21) domains. This study demonstrates that particularly TNBC tissues and cells display the prominent expression of IL-13Rα2. Furthermore, Pep-1-Phor21 induced the rapid necrosis of tumor cells expressing cell-surface IL-13Rα2. Notably, IL-13Rα2 expression was found to be epigenetically regulated in breast cancer cells in that the inhibition of histone deacetylase (HDAC) or DNA methyltransferase (DNMT) upregulated IL-13Rα2 expression, thereby sensitizing them to Pep-1-Phor21. IL-13Rα2-negative non-malignant cells were refractory to these epigenetic effects. Consistent with its cytolytic activity, Pep-1-Phor21 readily destroyed IL-13Rα2-expressing breast cancer spheroids with HDAC or DNMT inhibition, further enhancing cytolytic activity. Therefore, the Pep-1-Phor21-mediated targeting of IL-13Rα2 is a potentially novel therapeutic strategy for TNBC. Given that tumor cells can be selectively sensitized to Pep-1-Phor21 via the epigenetic up-regulation of IL-13Rα2, a combined adjuvant approach involving Pep-1-Phor21 and epigenetic inhibitors may be an effective strategy.
published_date 2023-05-16T13:42:32Z
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