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Antitumor Effects of PRMT5 Inhibition in Sarcomas

Patients with advanced soft-tissue sarcomas (STS) have few therapeutic options. Protein arginine methyltransferase 5 (PRMT5), an anticancer target, has been extensively investigated in recent years in epithelial tumors. To date, no data related to the biological role of PRMT5 inhibition and its pote...

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Autores principales: Verbeke, Stéphanie, Bourdon, Aurélien, Guegan, Jean-Philippe, Leroy, Laura, Chaire, Vanessa, Richard, Elodie, Bessede, Alban, Italiano, Antoine
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621483/
https://www.ncbi.nlm.nih.gov/pubmed/37861293
http://dx.doi.org/10.1158/2767-9764.CRC-23-0239
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author Verbeke, Stéphanie
Bourdon, Aurélien
Guegan, Jean-Philippe
Leroy, Laura
Chaire, Vanessa
Richard, Elodie
Bessede, Alban
Italiano, Antoine
author_facet Verbeke, Stéphanie
Bourdon, Aurélien
Guegan, Jean-Philippe
Leroy, Laura
Chaire, Vanessa
Richard, Elodie
Bessede, Alban
Italiano, Antoine
author_sort Verbeke, Stéphanie
collection PubMed
description Patients with advanced soft-tissue sarcomas (STS) have few therapeutic options. Protein arginine methyltransferase 5 (PRMT5), an anticancer target, has been extensively investigated in recent years in epithelial tumors. To date, no data related to the biological role of PRMT5 inhibition and its potential effect as a treatment in STS have been reported. To investigate the therapeutic potential of PRMT5 targeting in STS, we first evaluated the prognostic value of PRMT5 expression in two different cohorts of patients with STS. We then used the potent and selective GSK3326595 (GSK595) compound to investigate the antitumor effect of the pharmacologic inhibition of PRMT5 in vitro via MTT, apoptosis, cell cycle, clonogenicity, and proliferation assays. In vivo studies were performed with two animal models to evaluate the effects of GSK595 on tumor growth. The mechanisms of action were investigated by RNA sequencing, metabolic pathway analysis, Western blotting, and glucose uptake/lactate production assays. High PRMT5 gene expression levels were significantly associated with worsened metastasis-free survival of patients with STS. GSK595 decreased the global symmetric dimethylarginine level, the proliferation rate and clonogenicity of STS cell lines in vitro and tumor growth in vivo. Moreover, PRMT5 inhibition regulated aerobic glycolysis through downregulation of key enzymes of glycolysis as well as glucose uptake and lactate production. The current study demonstrated that PRMT5 regulates STS cell metabolism and thus represents a potential therapeutic target for STS. Additional studies in diverse sarcoma subtypes will be essential to confirm and expand upon these findings. SIGNIFICANCE: STSs have limited therapeutic options. We show here the poor prognostic value of high PRMT5 expression in STS. Moreover, we demonstrate that the pharmacologic inhibition of PRMT5 has significant antitumor activity through the downregulation of glycolysis. Our findings support the clinical investigation of PRMT5 inhibition in STSs.
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spelling pubmed-106214832023-11-03 Antitumor Effects of PRMT5 Inhibition in Sarcomas Verbeke, Stéphanie Bourdon, Aurélien Guegan, Jean-Philippe Leroy, Laura Chaire, Vanessa Richard, Elodie Bessede, Alban Italiano, Antoine Cancer Res Commun Research Article Patients with advanced soft-tissue sarcomas (STS) have few therapeutic options. Protein arginine methyltransferase 5 (PRMT5), an anticancer target, has been extensively investigated in recent years in epithelial tumors. To date, no data related to the biological role of PRMT5 inhibition and its potential effect as a treatment in STS have been reported. To investigate the therapeutic potential of PRMT5 targeting in STS, we first evaluated the prognostic value of PRMT5 expression in two different cohorts of patients with STS. We then used the potent and selective GSK3326595 (GSK595) compound to investigate the antitumor effect of the pharmacologic inhibition of PRMT5 in vitro via MTT, apoptosis, cell cycle, clonogenicity, and proliferation assays. In vivo studies were performed with two animal models to evaluate the effects of GSK595 on tumor growth. The mechanisms of action were investigated by RNA sequencing, metabolic pathway analysis, Western blotting, and glucose uptake/lactate production assays. High PRMT5 gene expression levels were significantly associated with worsened metastasis-free survival of patients with STS. GSK595 decreased the global symmetric dimethylarginine level, the proliferation rate and clonogenicity of STS cell lines in vitro and tumor growth in vivo. Moreover, PRMT5 inhibition regulated aerobic glycolysis through downregulation of key enzymes of glycolysis as well as glucose uptake and lactate production. The current study demonstrated that PRMT5 regulates STS cell metabolism and thus represents a potential therapeutic target for STS. Additional studies in diverse sarcoma subtypes will be essential to confirm and expand upon these findings. SIGNIFICANCE: STSs have limited therapeutic options. We show here the poor prognostic value of high PRMT5 expression in STS. Moreover, we demonstrate that the pharmacologic inhibition of PRMT5 has significant antitumor activity through the downregulation of glycolysis. Our findings support the clinical investigation of PRMT5 inhibition in STSs. American Association for Cancer Research 2023-11-02 /pmc/articles/PMC10621483/ /pubmed/37861293 http://dx.doi.org/10.1158/2767-9764.CRC-23-0239 Text en © 2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by/4.0/This open access article is distributed under the Creative Commons Attribution 4.0 International (CC BY 4.0) license.
spellingShingle Research Article
Verbeke, Stéphanie
Bourdon, Aurélien
Guegan, Jean-Philippe
Leroy, Laura
Chaire, Vanessa
Richard, Elodie
Bessede, Alban
Italiano, Antoine
Antitumor Effects of PRMT5 Inhibition in Sarcomas
title Antitumor Effects of PRMT5 Inhibition in Sarcomas
title_full Antitumor Effects of PRMT5 Inhibition in Sarcomas
title_fullStr Antitumor Effects of PRMT5 Inhibition in Sarcomas
title_full_unstemmed Antitumor Effects of PRMT5 Inhibition in Sarcomas
title_short Antitumor Effects of PRMT5 Inhibition in Sarcomas
title_sort antitumor effects of prmt5 inhibition in sarcomas
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10621483/
https://www.ncbi.nlm.nih.gov/pubmed/37861293
http://dx.doi.org/10.1158/2767-9764.CRC-23-0239
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