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Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth

Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents...

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Autores principales: Delle Donne, Rossella, Iannucci, Rosa, Rinaldi, Laura, Roberto, Luca, Oliva, Maria A., Senatore, Emanuela, Borzacchiello, Domenica, Lignitto, Luca, Giurato, Giorgio, Rizzo, Francesca, Sellitto, Assunta, Chiuso, Francesco, Castaldo, Salvatore, Scala, Giovanni, Campani, Virginia, Nele, Valeria, De Rosa, Giuseppe, D’Ambrosio, Chiara, Garbi, Corrado, Scaloni, Andrea, Weisz, Alessandro, Ambrosino, Concetta, Arcella, Antonella, Feliciello, Antonio
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345969/
https://www.ncbi.nlm.nih.gov/pubmed/35918402
http://dx.doi.org/10.1038/s42003-022-03639-8
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author Delle Donne, Rossella
Iannucci, Rosa
Rinaldi, Laura
Roberto, Luca
Oliva, Maria A.
Senatore, Emanuela
Borzacchiello, Domenica
Lignitto, Luca
Giurato, Giorgio
Rizzo, Francesca
Sellitto, Assunta
Chiuso, Francesco
Castaldo, Salvatore
Scala, Giovanni
Campani, Virginia
Nele, Valeria
De Rosa, Giuseppe
D’Ambrosio, Chiara
Garbi, Corrado
Scaloni, Andrea
Weisz, Alessandro
Ambrosino, Concetta
Arcella, Antonella
Feliciello, Antonio
author_facet Delle Donne, Rossella
Iannucci, Rosa
Rinaldi, Laura
Roberto, Luca
Oliva, Maria A.
Senatore, Emanuela
Borzacchiello, Domenica
Lignitto, Luca
Giurato, Giorgio
Rizzo, Francesca
Sellitto, Assunta
Chiuso, Francesco
Castaldo, Salvatore
Scala, Giovanni
Campani, Virginia
Nele, Valeria
De Rosa, Giuseppe
D’Ambrosio, Chiara
Garbi, Corrado
Scaloni, Andrea
Weisz, Alessandro
Ambrosino, Concetta
Arcella, Antonella
Feliciello, Antonio
author_sort Delle Donne, Rossella
collection PubMed
description Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, the UPS represents a potentially valuable target for GBM treatment. Using an integrated approach that includes proteomics, transcriptomics and metabolic profiling, we identify praja2, a RING E3 ubiquitin ligase, as the key component of a signaling network that regulates GBM cell growth and metabolism. Praja2 is preferentially expressed in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1). Mechanistically, we found that praja2 ubiquitylates and degrades the kinase suppressor of Ras 2 (KSR2). As a consequence, praja2 restrains the activity of downstream AMP-dependent protein kinase in GBM cells and attenuates the oxidative metabolism. Delivery in the brain of siRNA targeting praja2 by transferrin-targeted self-assembling nanoparticles (SANPs) prevented KSR2 degradation and inhibited GBM growth, reducing the size of the tumor and prolonging the survival rate of treated mice. These data identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target to suppress GBM growth.
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spelling pubmed-93459692022-08-04 Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth Delle Donne, Rossella Iannucci, Rosa Rinaldi, Laura Roberto, Luca Oliva, Maria A. Senatore, Emanuela Borzacchiello, Domenica Lignitto, Luca Giurato, Giorgio Rizzo, Francesca Sellitto, Assunta Chiuso, Francesco Castaldo, Salvatore Scala, Giovanni Campani, Virginia Nele, Valeria De Rosa, Giuseppe D’Ambrosio, Chiara Garbi, Corrado Scaloni, Andrea Weisz, Alessandro Ambrosino, Concetta Arcella, Antonella Feliciello, Antonio Commun Biol Article Glioblastoma multiforme (GBM) is the most frequent and aggressive form of primary brain tumor in the adult population; its high recurrence rate and resistance to current therapeutics urgently demand a better therapy. Regulation of protein stability by the ubiquitin proteasome system (UPS) represents an important control mechanism of cell growth. UPS deregulation is mechanistically linked to the development and progression of a variety of human cancers, including GBM. Thus, the UPS represents a potentially valuable target for GBM treatment. Using an integrated approach that includes proteomics, transcriptomics and metabolic profiling, we identify praja2, a RING E3 ubiquitin ligase, as the key component of a signaling network that regulates GBM cell growth and metabolism. Praja2 is preferentially expressed in primary GBM lesions expressing the wild-type isocitrate dehydrogenase 1 gene (IDH1). Mechanistically, we found that praja2 ubiquitylates and degrades the kinase suppressor of Ras 2 (KSR2). As a consequence, praja2 restrains the activity of downstream AMP-dependent protein kinase in GBM cells and attenuates the oxidative metabolism. Delivery in the brain of siRNA targeting praja2 by transferrin-targeted self-assembling nanoparticles (SANPs) prevented KSR2 degradation and inhibited GBM growth, reducing the size of the tumor and prolonging the survival rate of treated mice. These data identify praja2 as an essential regulator of cancer cell metabolism, and as a potential therapeutic target to suppress GBM growth. Nature Publishing Group UK 2022-08-02 /pmc/articles/PMC9345969/ /pubmed/35918402 http://dx.doi.org/10.1038/s42003-022-03639-8 Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open Access This 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 license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license 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 license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Delle Donne, Rossella
Iannucci, Rosa
Rinaldi, Laura
Roberto, Luca
Oliva, Maria A.
Senatore, Emanuela
Borzacchiello, Domenica
Lignitto, Luca
Giurato, Giorgio
Rizzo, Francesca
Sellitto, Assunta
Chiuso, Francesco
Castaldo, Salvatore
Scala, Giovanni
Campani, Virginia
Nele, Valeria
De Rosa, Giuseppe
D’Ambrosio, Chiara
Garbi, Corrado
Scaloni, Andrea
Weisz, Alessandro
Ambrosino, Concetta
Arcella, Antonella
Feliciello, Antonio
Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title_full Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title_fullStr Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title_full_unstemmed Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title_short Targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
title_sort targeted inhibition of ubiquitin signaling reverses metabolic reprogramming and suppresses glioblastoma growth
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9345969/
https://www.ncbi.nlm.nih.gov/pubmed/35918402
http://dx.doi.org/10.1038/s42003-022-03639-8
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