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GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells

Amino acid availability is crucial for cancer cells’ survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid po...

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Autores principales: Loxha, Lorent, Ibrahim, Nurul Khalida, Stasche, Anna Sophie, Cinar, Büsra, Dolgner, Tim, Niessen, Julia, Schreek, Sabine, Fehlhaber, Beate, Forster, Michael, Stanulla, Martin, Hinze, Laura
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10488213/
https://www.ncbi.nlm.nih.gov/pubmed/37686063
http://dx.doi.org/10.3390/ijms241713260
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author Loxha, Lorent
Ibrahim, Nurul Khalida
Stasche, Anna Sophie
Cinar, Büsra
Dolgner, Tim
Niessen, Julia
Schreek, Sabine
Fehlhaber, Beate
Forster, Michael
Stanulla, Martin
Hinze, Laura
author_facet Loxha, Lorent
Ibrahim, Nurul Khalida
Stasche, Anna Sophie
Cinar, Büsra
Dolgner, Tim
Niessen, Julia
Schreek, Sabine
Fehlhaber, Beate
Forster, Michael
Stanulla, Martin
Hinze, Laura
author_sort Loxha, Lorent
collection PubMed
description Amino acid availability is crucial for cancer cells’ survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation.
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spelling pubmed-104882132023-09-09 GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells Loxha, Lorent Ibrahim, Nurul Khalida Stasche, Anna Sophie Cinar, Büsra Dolgner, Tim Niessen, Julia Schreek, Sabine Fehlhaber, Beate Forster, Michael Stanulla, Martin Hinze, Laura Int J Mol Sci Article Amino acid availability is crucial for cancer cells’ survivability. Leukemia and colorectal cancer cells have been shown to resist asparagine depletion by utilizing GSK3-dependent proteasomal degradation, termed the Wnt-dependent stabilization of proteins (Wnt/STOP), to replenish their amino acid pool. The inhibition of GSK3α halts the sourcing of amino acids, which subsequently leads to cancer cell vulnerability toward asparaginase therapy. However, resistance toward GSK3α-mediated protein breakdown can occur, whose underlying mechanism is poorly understood. Here, we set out to define the mechanisms driving dependence toward this degradation machinery upon asparagine starvation in cancer cells. We show the independence of known stress response pathways including the integrated stress response mediated with GCN2. Additionally, we demonstrate the independence of changes in cell cycle progression and expression levels of the asparagine-synthesizing enzyme ASNS. Instead, RNA sequencing revealed that GSK3α inhibition and asparagine starvation leads to the temporally dynamic downregulation of distinct ribosomal proteins, which have been shown to display anti-proliferative functions. Using a CRISPR/Cas9 viability screen, we demonstrate that the downregulation of these specific ribosomal proteins can rescue cell death upon GSK3α inhibition and asparagine starvation. Thus, our findings suggest the vital role of the previously unrecognized regulation of ribosomal proteins in bridging GSK3α activity and tolerance of asparagine starvation. MDPI 2023-08-26 /pmc/articles/PMC10488213/ /pubmed/37686063 http://dx.doi.org/10.3390/ijms241713260 Text en © 2023 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
Loxha, Lorent
Ibrahim, Nurul Khalida
Stasche, Anna Sophie
Cinar, Büsra
Dolgner, Tim
Niessen, Julia
Schreek, Sabine
Fehlhaber, Beate
Forster, Michael
Stanulla, Martin
Hinze, Laura
GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title_full GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title_fullStr GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title_full_unstemmed GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title_short GSK3α Regulates Temporally Dynamic Changes in Ribosomal Proteins upon Amino Acid Starvation in Cancer Cells
title_sort gsk3α regulates temporally dynamic changes in ribosomal proteins upon amino acid starvation in cancer cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10488213/
https://www.ncbi.nlm.nih.gov/pubmed/37686063
http://dx.doi.org/10.3390/ijms241713260
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