title: Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells.
abstract: Soft tissue sarcomas (STS) are malignant tumors of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumors with more than 50 different subtypes. The Wnt signaling pathway is involved in the development and in the regulation, self-renewal, and differentiation of mesenchymal stem cells, and plays a role in sarcomagenesis. In this study, we have tested pharmacologic inhibition of Wnt signaling mediated by disruption of TCF/β-catenin binding and AXIN stabilization, being the first strategy more efficient in reducing cell viability and downstream effects. We have shown that disruption of TCF/β-catenin binding with PKF118-310 producesin vitroantitumor activity in a panel of prevalent representative STS cell lines and primary cultures. At the molecular level, PKF118-310 treatment reduced β-catenin nuclear localization, reporter activity, and target genes, resulting in an increase in apoptosis. Importantly, combination of PKF118-310 with doxorubicin resulted in enhanced reduction of cell viability, suggesting that Wnt inhibition could be a new combination regime in these patients. Our findings support the usefulness of Wnt inhibitors as new therapeutic strategies for the prevalent STS.Mol Cancer Ther; 16(6); 1166-76. ©2017 AACR.
authors.affiliation: Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain.
authors.forename: Esther
authors.initials: E
authors.lastname: Martinez-Font
authors.affiliation: Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.
authors.forename: Irene
authors.initials: I
authors.lastname: Felipe-Abrio
authors.affiliation: Molecular Oncology Laboratory, Fundación de Investigación, Hospital General Universitario de Valencia, Valencia, Spain.|Department of Pathology, Universitat de Valencia, Valencia, Spain.
authors.forename: Silvia
authors.initials: S
authors.lastname: Calabuig-Fariñas
authors.affiliation: Department of Pathology, Hospital Universitari Son Espases, Palma de Mallorca, Spain.
authors.forename: Rafael
authors.initials: R
authors.lastname: Ramos
authors.affiliation: Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain.|Department of Oncology, Hospital Universitari Son Espases, Palma de Mallorca, Spain.
authors.forename: Josefa
authors.initials: J
authors.lastname: Terrasa
authors.affiliation: Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain.|Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Spain.
authors.forename: Oliver
authors.initials: O
authors.lastname: Vögler
authors.affiliation: Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain.|Group of Clinical and Translational Research, Department of Biology, Institut Universitari d'Investigacions en Ciències de la Salut (IUNICS), University of the Balearic Islands, Spain.
authors.forename: Regina
authors.initials: R
authors.lastname: Alemany
authors.affiliation: Group of Molecular Oncology and New Therapies, Oncohematology and Genetics Department, Instituto de Biomedicina de Sevilla (IBiS), Sevilla, Spain.|Department of Oncology, Hospital Universitario Virgen del Rocío, Sevilla, Spain.
authors.forename: Javier
authors.initials: J
authors.lastname: Martín-Broto
authors.affiliation: Group of Advanced Therapies and Biomarkers in Clinical Oncology, Institut d'Investigació Sanitària de Palma (IdISPa), Palma de Mallorca, Spain. antonia.obrador@ssib.es.|Department of Oncology, Hospital Universitari Son Espases, Palma de Mallorca, Spain.
authors.forename: Antònia
authors.initials: A
authors.lastname: Obrador-Hevia
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects; D002453:Cell Cycle; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D004357:Drug Synergism; D006801:Humans; D011485:Protein Binding; D011744:Pyrimidinones / Q000494:pharmacology; D012509:Sarcoma / Q000378:metabolism*; D051820:TCF Transcription Factors / Q000378:metabolism*; D014227:Triazines / Q000494:pharmacology; D060449:Wnt Signaling Pathway / Q000187:drug effects; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; C548732:PKF118-310; D011744:Pyrimidinones; D051820:TCF Transcription Factors; D014227:Triazines; D051176:beta Catenin; D004317:Doxorubicin