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Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells

Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms det...

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Autores principales: Chen, Oleg, Manig, Friederike, Lehmann, Loreen, Sorour, Nagwa, Löck, Steffen, Yu, Zhanru, Dubrovska, Anna, Baumann, Michael, Kessler, Benedikt M., Stasyk, Oleh, Kunz-Schughart, Leoni A.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Springer International Publishing 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004506/
https://www.ncbi.nlm.nih.gov/pubmed/33230565
http://dx.doi.org/10.1007/s00018-020-03704-7
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author Chen, Oleg
Manig, Friederike
Lehmann, Loreen
Sorour, Nagwa
Löck, Steffen
Yu, Zhanru
Dubrovska, Anna
Baumann, Michael
Kessler, Benedikt M.
Stasyk, Oleh
Kunz-Schughart, Leoni A.
author_facet Chen, Oleg
Manig, Friederike
Lehmann, Loreen
Sorour, Nagwa
Löck, Steffen
Yu, Zhanru
Dubrovska, Anna
Baumann, Michael
Kessler, Benedikt M.
Stasyk, Oleh
Kunz-Schughart, Leoni A.
author_sort Chen, Oleg
collection PubMed
description Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03704-7) contains supplementary material, which is available to authorized users.
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spelling pubmed-80045062021-04-16 Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells Chen, Oleg Manig, Friederike Lehmann, Loreen Sorour, Nagwa Löck, Steffen Yu, Zhanru Dubrovska, Anna Baumann, Michael Kessler, Benedikt M. Stasyk, Oleh Kunz-Schughart, Leoni A. Cell Mol Life Sci Original Article Arginine deprivation therapy (ADT) is a new metabolic targeting approach with high therapeutic potential for various solid cancers. Combination of ADT with low doses of the natural arginine analog canavanine effectively sensitizes malignant cells to irradiation. However, the molecular mechanisms determining the sensitivity of intrinsically non-auxotrophic cancers to arginine deficiency are still poorly understood. We here show for the first time that arginine deficiency is accompanied by global metabolic changes and protein/membrane breakdown, and results in the induction of specific, more or less pronounced (severe vs. mild) ER stress responses in head and neck squamous cell carcinoma (HNSCC) cells that differ in their intrinsic ADT sensitivity. Combination of ADT with canavanine triggered catastrophic ER stress via the eIF2α-ATF4(GADD34)-CHOP pathway, thereby inducing apoptosis; the same signaling arm was irrelevant in ADT-related radiosensitization. The particular strong supra-additive effect of ADT, canavanine and irradiation in both intrinsically more and less sensitive cancer cells supports the rational of ER stress pathways as novel target for improving multi-modal metabolic anti-cancer therapy. ELECTRONIC SUPPLEMENTARY MATERIAL: The online version of this article (10.1007/s00018-020-03704-7) contains supplementary material, which is available to authorized users. Springer International Publishing 2020-11-23 2021 /pmc/articles/PMC8004506/ /pubmed/33230565 http://dx.doi.org/10.1007/s00018-020-03704-7 Text en © The Author(s) 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.
spellingShingle Original Article
Chen, Oleg
Manig, Friederike
Lehmann, Loreen
Sorour, Nagwa
Löck, Steffen
Yu, Zhanru
Dubrovska, Anna
Baumann, Michael
Kessler, Benedikt M.
Stasyk, Oleh
Kunz-Schughart, Leoni A.
Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title_full Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title_fullStr Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title_full_unstemmed Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title_short Dual role of ER stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
title_sort dual role of er stress in response to metabolic co-targeting and radiosensitivity in head and neck cancer cells
topic Original Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004506/
https://www.ncbi.nlm.nih.gov/pubmed/33230565
http://dx.doi.org/10.1007/s00018-020-03704-7
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