Contributors: Grupo Español de Investigación en Sarcomas; Fundación Mari Paz Jiménez Casado; Ministerio de Trabajo, Migraciones y Seguridad Social (España); [Martinez-Font,E; Pérez-Capó,M; Garcías,C; Terrasa,J; Vögler,O; Alemany,R; 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, Palma, Spain. [Martinez-Font,E; Luna,P; Terrasa,J] Medical Oncology Department, Son Espases University Hospital, Palma, Spain. [Ramos,R] Pathology Department, Son Espases University Hospital, Palma, Spain. [Felipe,I] Epithelial Carcinogenesis Group, Spanish National Cancer Research Centre-CNIO, Madrid, Spain. [Martín-Broto,J] Medical Oncology Department, University Hospital Virgen del Rocío, Sevilla, Spain. [Martín-Broto,J] Institute of Biomedicine of Sevilla, IBIS, HUVR, CSIC, Universidad de Sevilla, Sevilla, Spain. [Vögler,O, Alemany,R] Group of Clinical and Translational Research, Department of Biology, University of the Balearic Islands, Palma, Spain. [Obrador-Hevia,A] Molecular Diagnosis Unit, Son Espases University Hospital, Palma, Spain.; This study was financed by Grupo Español de Investigación en Sarcomas (GEIS) and Fundación Mari Paz Jiménez Casado. MPC is supported by Programa Estrategia de Emprendimiento y Empleo Joven, Garantía Juvenil (Ministerio de Trabajo, Migraciones y Seguridad Social-SOIB).; Grupo Español de Investigación en Sarcomas (GEIS); Ministerio de Trabajo, Migraciones y Seguridad Social-SOIB
نبذة مختصرة : © 2020 by the authors.
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.
This study was financed by Grupo Español de Investigación en Sarcomas (GEIS) and Fundación Mari Paz Jiménez Casado. MPC is supported by Programa Estrategia de Emprendimiento y Empleo Joven, Garantía Juvenil (Ministerio de Trabajo, Migraciones y Seguridad Social-SOIB).
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