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Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth

Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor...

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Autores principales: Caron, Jennifer M., Han, Xianghua, Lary, Christine W., Sathyanarayana, Pradeep, Remick, Scot C., Ernstoff, Marc S., Herlyn, Meenhard, Brooks, Peter C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: D.A. Spandidos 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868893/
https://www.ncbi.nlm.nih.gov/pubmed/36633146
http://dx.doi.org/10.3892/or.2023.8481
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author Caron, Jennifer M.
Han, Xianghua
Lary, Christine W.
Sathyanarayana, Pradeep
Remick, Scot C.
Ernstoff, Marc S.
Herlyn, Meenhard
Brooks, Peter C.
author_facet Caron, Jennifer M.
Han, Xianghua
Lary, Christine W.
Sathyanarayana, Pradeep
Remick, Scot C.
Ernstoff, Marc S.
Herlyn, Meenhard
Brooks, Peter C.
author_sort Caron, Jennifer M.
collection PubMed
description Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro- and anti-tumorigenic functions in a cell type-dependent manner. Therefore, designing strategies that block pro-tumorigenic signaling, without impeding anti-tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which β3-integrin-mediated binding to a secreted RGDKGE-containing collagen fragment stimulates an autocrine-like signaling pathway that differentially governs the activity of both YAP and (protein kinase-A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD-L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine-like signaling pathway that may provide tumor cells with the ability to regulate PD-L1, but our findings may also help in the development of more effective strategies to control pro-tumorigenic β3-integrin signaling without disrupting its tumor suppressive functions in other cellular compartments.
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spelling pubmed-98688932023-02-03 Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth Caron, Jennifer M. Han, Xianghua Lary, Christine W. Sathyanarayana, Pradeep Remick, Scot C. Ernstoff, Marc S. Herlyn, Meenhard Brooks, Peter C. Oncol Rep Articles Structural alterations of collagen impact signaling that helps control tumor progression and the responses to therapeutic intervention. Integrins represent a class of receptors that include members that mediate collagen signaling. However, a strategy of directly targeting integrins to control tumor growth has demonstrated limited activity in the clinical setting. New molecular understanding of integrins have revealed that these receptors can regulate both pro- and anti-tumorigenic functions in a cell type-dependent manner. Therefore, designing strategies that block pro-tumorigenic signaling, without impeding anti-tumorigenic functions, may lead to development of more effective therapies. In the present study, evidence was provided for a novel signaling cascade in which β3-integrin-mediated binding to a secreted RGDKGE-containing collagen fragment stimulates an autocrine-like signaling pathway that differentially governs the activity of both YAP and (protein kinase-A) PKA, ultimately leading to alterations in the levels of immune checkpoint molecule PD-L1 by a proteasome dependent mechanism. Selectively targeting this collagen fragment, reduced nuclear YAP levels, and enhanced PKA and proteasome activity, while also exhibiting significant antitumor activity in vivo. The present findings not only provided new mechanistic insight into a previously unknown autocrine-like signaling pathway that may provide tumor cells with the ability to regulate PD-L1, but our findings may also help in the development of more effective strategies to control pro-tumorigenic β3-integrin signaling without disrupting its tumor suppressive functions in other cellular compartments. D.A. Spandidos 2023-01-12 /pmc/articles/PMC9868893/ /pubmed/36633146 http://dx.doi.org/10.3892/or.2023.8481 Text en Copyright: © Caron et al. https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivs License (https://creativecommons.org/licenses/by-nc-nd/4.0/) , which permits use and distribution in any medium, provided the original work is properly cited, the use is non-commercial and no modifications or adaptations are made.
spellingShingle Articles
Caron, Jennifer M.
Han, Xianghua
Lary, Christine W.
Sathyanarayana, Pradeep
Remick, Scot C.
Ernstoff, Marc S.
Herlyn, Meenhard
Brooks, Peter C.
Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title_full Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title_fullStr Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title_full_unstemmed Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title_short Targeting the secreted RGDKGE collagen fragment reduces PD‑L1 by a proteasome‑dependent mechanism and inhibits tumor growth
title_sort targeting the secreted rgdkge collagen fragment reduces pd‑l1 by a proteasome‑dependent mechanism and inhibits tumor growth
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9868893/
https://www.ncbi.nlm.nih.gov/pubmed/36633146
http://dx.doi.org/10.3892/or.2023.8481
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