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

Autor:	Antònia Obrador-Hevia, Irene Felipe, Rafael Yus Ramos, Marina Pérez-Capó, Carmen Garcías, Pablo Luna, Javier Martin-Broto, Esther Martinez-Font, Oliver Vögler, Regina Alemany, J. Terrasa
Přispěvatelé:	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
Jazyk:	angličtina
Rok vydání:	2020
Předmět:	0301 basic medicine Cancer Research PRI-724 Cell cycle checkpoint Trabectedina Phenomena and Processes::Genetic Phenomena::Genetic Processes::Gene Expression Regulation::Down-Regulation [Medical Subject Headings] medicine.disease_cause Organisms::Eukaryota::Animals::Chordata::Vertebrates::Mammals::Primates::Haplorhini::Catarrhini::Hominidae::Humans [Medical Subject Headings] 0302 clinical medicine Anatomy::Cells::Cells Cultured::Cell Line [Medical Subject Headings] Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms Glandular and Epithelial::Carcinoma::Adenocarcinoma [Medical Subject Headings] Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle [Medical Subject Headings] Diseases::Neoplasms::Neoplasms by Histologic Type::Neoplasms Connective and Soft Tissue [Medical Subject Headings] Phenomena and Processes::Chemical Phenomena::Chemical Processes::Biochemical Processes::Signal Transduction::Wnt Signaling Pathway [Medical Subject Headings] Soft tissue sarcoma Phenomena and Processes::Physiological Phenomena::Physiological Processes::Growth and Development::Growth::Cell Growth Processes::Cell Proliferation [Medical Subject Headings] Wnt signaling pathway Sarcoma Cell cycle Diseases::Neoplasms::Neoplastic Processes::Carcinogenesis [Medical Subject Headings] lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens Diseases::Neoplasms::Neoplasms by Site::Endocrine Gland Neoplasms::Ovarian Neoplasms [Medical Subject Headings] Oncology 030220 oncology & carcinogenesis soft tissue sarcoma CDC25A Information Science::Information Science::Information Storage and Retrieval::Databases as Topic::Databases Factual::Databases Genetic::Databases Nucleic Acid [Medical Subject Headings] Vía de señalización Wnt Biology lcsh:RC254-282 Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Cycle::Cell Cycle Checkpoints [Medical Subject Headings] Article 03 medical and health sciences Downregulation and upregulation Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Survival [Medical Subject Headings] medicine Chemicals and Drugs::Nucleic Acids Nucleotides and Nucleosides::Antisense Elements (Genetics)::RNA Antisense::RNA Small Interfering [Medical Subject Headings] Cell growth beta-catenin Chemicals and Drugs::Nucleic Acids Nucleotides and Nucleosides::Nucleic Acids::RNA::RNA Messenger [Medical Subject Headings] β-catenin Phenomena and Processes::Cell Physiological Phenomena::Cell Physiological Processes::Cell Death [Medical Subject Headings] Wnt signaling Chemicals and Drugs::Amino Acids Peptides and Proteins::Proteins::Cytoskeletal Proteins::Catenins [Medical Subject Headings] Diseases::Neoplasms::Neoplasms by Site::Digestive System Neoplasms::Pancreatic Neoplasms [Medical Subject Headings] 030104 developmental biology Catenin Cancer research Chemicals and Drugs::Carbohydrates::Glycosides::Aminoglycosides::Anthracyclines::Daunorubicin::Doxorubicin [Medical Subject Headings] Beta Catenina Carcinogenesis Trabectedin
Zdroj:	Cancers Volume 12 Issue 9 Repisalud Instituto de Salud Carlos III (ISCIII) Cancers, Vol 12, Iss 2556, p 2556 (2020) Digital.CSIC. Repositorio Institucional del CSIC instname
ISSN:	2072-6694
DOI:	10.3390/cancers12092556
Popis:	© 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).
Databáze:	OpenAIRE
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