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

Autor: Martinez-Font E; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Medical Oncology Department, Son Espases University Hospital, 07120 Palma, Spain., Pérez-Capó M; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Medical Oncology Department, Son Espases University Hospital, 07120 Palma, Spain., Ramos R; Pathology Department, Son Espases University Hospital, 07120 Palma, Spain., Felipe I; Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, 28029 Madrid, Spain., Garcías C; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Medical Oncology Department, Son Espases University Hospital, 07120 Palma, Spain., Luna P; Medical Oncology Department, Son Espases University Hospital, 07120 Palma, Spain., Terrasa J; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Medical Oncology Department, Son Espases University Hospital, 07120 Palma, Spain., Martín-Broto J; Medical Oncology Department, University Hospital Virgen del Rocío, 41013 Sevilla, Spain.; Institute of Biomedicine of Sevilla, IBIS, HUVR, CSIC, Universidad de Sevilla, 41013 Sevilla, Spain., Vögler O; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Group of Clinical and Translational Research, Department of Biology, University of the Balearic Islands, 07122 Palma, Spain., Alemany R; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Group of Clinical and Translational Research, Department of Biology, University of the Balearic Islands, 07122 Palma, Spain., Obrador-Hevia A; Group of Advanced Therapies and Biomarkers in Clinical Oncology, Health Research Institute of the Balearic Islands (IdISBa-IUNICS), Son Espases University Hospital, 07120 Palma, Spain.; Molecular Diagnosis Unit, Son Espases University Hospital, 07120 Palma, Spain.
Jazyk: angličtina
Zdroj: Cancers [Cancers (Basel)] 2020 Sep 08; Vol. 12 (9). Date of Electronic Publication: 2020 Sep 08.
DOI: 10.3390/cancers12092556
Abstrakt: 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.
Databáze: MEDLINE
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