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Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas

SIMPLE SUMMARY: Growing evidence suggests that Wnt signaling may be crucial for tumorigenesis and progression of soft tissue sarcomas (STS). Inhibitors of this pathway are currently in clinical trials or pre-clinical studies in order to validate its utility in different neoplasia. One of this inhibi...

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Autores principales: Martinez-Font, Esther, Pérez-Capó, Marina, Ramos, Rafael, Felipe, Irene, Garcías, Carmen, Luna, Pablo, Terrasa, Josefa, Martín-Broto, Javier, Vögler, Oliver, Alemany, Regina, Obrador-Hevia, Antònia
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564873/
https://www.ncbi.nlm.nih.gov/pubmed/32911761
http://dx.doi.org/10.3390/cancers12092556
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author Martinez-Font, Esther
Pérez-Capó, Marina
Ramos, Rafael
Felipe, Irene
Garcías, Carmen
Luna, Pablo
Terrasa, Josefa
Martín-Broto, Javier
Vögler, Oliver
Alemany, Regina
Obrador-Hevia, Antònia
author_facet Martinez-Font, Esther
Pérez-Capó, Marina
Ramos, Rafael
Felipe, Irene
Garcías, Carmen
Luna, Pablo
Terrasa, Josefa
Martín-Broto, Javier
Vögler, Oliver
Alemany, Regina
Obrador-Hevia, Antònia
author_sort Martinez-Font, Esther
collection PubMed
description SIMPLE SUMMARY: Growing evidence suggests that Wnt signaling may be crucial for tumorigenesis and progression of soft tissue sarcomas (STS). Inhibitors of this pathway are currently in clinical trials or pre-clinical studies in order to validate its utility in different neoplasia. One of this inhibitors, PRI-724, is showing promising results for advanced pancreatic adenocarcinoma or ovarian cancer. We found that PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates of soft tissue sarcomas cells in vitro. CDC25A, a target gene of Wnt signaling pathway, is essential for STS proliferation because its downregulation via siRNA was able to mimic the effect of PRT-724 on cell cycle arrest and evaluation of NCBI/GenBank data confirmed its overexpression in STS patients’ samples. Moreover, in vitro administration of PRI-724 along with standard STS chemotherapeutic drugs improved the efficacy of chemotherapy, suggesting that Wnt inhibition could be a promising new therapeutic strategy in STS. ABSTRACT: The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian cancer. Growing evidence suggests that Wnt signaling may also be crucial for tumorigenesis and progression of soft tissue sarcomas (STS), a malignant neoplasm with few therapeutic options at an advanced state. Our study with several STS cell lines and primary cultures shows that inhibition of Wnt/β-catenin signaling with PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates. TCF/β-catenin-mediated transcriptional activity is decreased in treated cells, leading to downregulation of its target genes CCND1 and CDC25A. The latter was critical because its downregulation via siRNA was able to mimic the effect of PRI-724 on cell cycle arrest and cell death induction. An evaluation of NCBI/GenBank data confirmed that CDC25A mRNA is elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergistic manner according to isobolographic analysis, suggesting that Wnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS.
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spelling pubmed-75648732020-10-26 Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas Martinez-Font, Esther Pérez-Capó, Marina Ramos, Rafael Felipe, Irene Garcías, Carmen Luna, Pablo Terrasa, Josefa Martín-Broto, Javier Vögler, Oliver Alemany, Regina Obrador-Hevia, Antònia Cancers (Basel) Article SIMPLE SUMMARY: Growing evidence suggests that Wnt signaling may be crucial for tumorigenesis and progression of soft tissue sarcomas (STS). Inhibitors of this pathway are currently in clinical trials or pre-clinical studies in order to validate its utility in different neoplasia. One of this inhibitors, PRI-724, is showing promising results for advanced pancreatic adenocarcinoma or ovarian cancer. We found that PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates of soft tissue sarcomas cells in vitro. CDC25A, a target gene of Wnt signaling pathway, is essential for STS proliferation because its downregulation via siRNA was able to mimic the effect of PRT-724 on cell cycle arrest and evaluation of NCBI/GenBank data confirmed its overexpression in STS patients’ samples. Moreover, in vitro administration of PRI-724 along with standard STS chemotherapeutic drugs improved the efficacy of chemotherapy, suggesting that Wnt inhibition could be a promising new therapeutic strategy in STS. ABSTRACT: The Wnt signaling pathway is an important cellular mechanism for regulating differentiation processes as well as cell cycle events, and different inhibitors of this pathway, for example, PRI-724, are showing promising results in clinical trials for treatment of advanced pancreatic adenocarcinoma or ovarian cancer. Growing evidence suggests that Wnt signaling may also be crucial for tumorigenesis and progression of soft tissue sarcomas (STS), a malignant neoplasm with few therapeutic options at an advanced state. Our study with several STS cell lines and primary cultures shows that inhibition of Wnt/β-catenin signaling with PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates. TCF/β-catenin-mediated transcriptional activity is decreased in treated cells, leading to downregulation of its target genes CCND1 and CDC25A. The latter was critical because its downregulation via siRNA was able to mimic the effect of PRI-724 on cell cycle arrest and cell death induction. An evaluation of NCBI/GenBank data confirmed that CDC25A mRNA is elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergistic manner according to isobolographic analysis, suggesting that Wnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS. MDPI 2020-09-08 /pmc/articles/PMC7564873/ /pubmed/32911761 http://dx.doi.org/10.3390/cancers12092556 Text en © 2020 by the authors. 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 (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Martinez-Font, Esther
Pérez-Capó, Marina
Ramos, Rafael
Felipe, Irene
Garcías, Carmen
Luna, Pablo
Terrasa, Josefa
Martín-Broto, Javier
Vögler, Oliver
Alemany, Regina
Obrador-Hevia, Antònia
Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title_full Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title_fullStr Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title_full_unstemmed Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title_short Impact of Wnt/β-Catenin Inhibition on Cell Proliferation through CDC25A Downregulation in Soft Tissue Sarcomas
title_sort impact of wnt/β-catenin inhibition on cell proliferation through cdc25a downregulation in soft tissue sarcomas
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7564873/
https://www.ncbi.nlm.nih.gov/pubmed/32911761
http://dx.doi.org/10.3390/cancers12092556
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