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Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1

Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an...

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Autores principales: Blagojevic, Biljana, Almouhanna, Fadi, Poschet, Gernot, Wölfl, Stefan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9736985/
https://www.ncbi.nlm.nih.gov/pubmed/36497120
http://dx.doi.org/10.3390/cells11233863
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author Blagojevic, Biljana
Almouhanna, Fadi
Poschet, Gernot
Wölfl, Stefan
author_facet Blagojevic, Biljana
Almouhanna, Fadi
Poschet, Gernot
Wölfl, Stefan
author_sort Blagojevic, Biljana
collection PubMed
description Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming.
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spelling pubmed-97369852022-12-11 Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1 Blagojevic, Biljana Almouhanna, Fadi Poschet, Gernot Wölfl, Stefan Cells Article Targeting cancer metabolism has become one of the strategies for a rational anti-tumor therapy. However, cellular plasticity, driven by a major regulator of cellular growth and metabolism, mTORC1, often leads toward treatment resistance. Sestrin2, a stress-inducible protein, has been described as an mTORC1 inhibitor upon various types of stress signals. Immune assays and online measurements of cellular bioenergetics were employed to investigate the nature of Sestrin2 regulation, and finally, by silencing the SESN2 gene, to identify the role of induced Sestrin2 upon a single amino acid deprivation in cancer cells of various origins. Our data suggest that a complex interplay of either oxidative, energetic, nutritional stress, or in combination, play a role in Sestrin2 regulation upon single amino acid deprivation. Therefore, cellular metabolic background and sequential metabolic response dictate Sestrin2 expression in the absence of an amino acid. While deprivations of essential amino acids uniformly induce Sestrin2 levels, non-essential amino acids regulate Sestrin2 differently, drawing a characteristic Sestrin2 expression fingerprint, which could serve as a first indication of the underlying cellular vulnerability. Finally, we show that canonical GCN2-ATF4-mediated Sestrin2 induction leads to mTORC1 inhibition only in amino acid auxotroph cells, where the amino acid cannot be replenished by metabolic reprogramming. MDPI 2022-11-30 /pmc/articles/PMC9736985/ /pubmed/36497120 http://dx.doi.org/10.3390/cells11233863 Text en © 2022 by the authors. https://creativecommons.org/licenses/by/4.0/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/).
spellingShingle Article
Blagojevic, Biljana
Almouhanna, Fadi
Poschet, Gernot
Wölfl, Stefan
Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title_full Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title_fullStr Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title_full_unstemmed Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title_short Cell Type-Specific Metabolic Response to Amino Acid Starvation Dictates the Role of Sestrin2 in Regulation of mTORC1
title_sort cell type-specific metabolic response to amino acid starvation dictates the role of sestrin2 in regulation of mtorc1
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9736985/
https://www.ncbi.nlm.nih.gov/pubmed/36497120
http://dx.doi.org/10.3390/cells11233863
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