Disruption of TCF/β-Catenin Binding Impairs Wnt Signaling and Induces Apoptosis in Soft Tissue Sarcoma Cells

• Published in: Molecular cancer therapeutics Vol. 16; no. 6; pp. 1166 - 1176
• Main Authors: Martinez-Font, Esther, Felipe-Abrio, Irene, Calabuig-Fariñas, Silvia, Ramos, Rafael, Terrasa, Josefa, Vögler, Oliver, Alemany, Regina, Martín-Broto, Javier, Obrador-Hevia, Antònia
• Format: Journal Article
• Language: English
• Published: United States American Association for Cancer Research Inc 01.06.2017
• Subjects: Anticancer properties; Antineoplastic Agents - pharmacology; Antitumor activity; Apoptosis; Apoptosis - drug effects; beta Catenin - metabolism; Binding; Cell Cycle; Cell Line, Tumor; Cell Proliferation; Cell self-renewal; Cell Survival - drug effects; Disruption; Doxorubicin; Doxorubicin - pharmacology; Drug Synergism; Embryos; Humans; Inhibition; Localization; Mesenchyme; Pharmacology; Protein Binding; Pyrimidinones - pharmacology; Sarcoma; Sarcoma - metabolism; Signal transduction; Signaling; Soft tissue sarcoma; Stem cells; TCF Transcription Factors - metabolism; Triazines - pharmacology; Tumors; Wnt protein; Wnt Signaling Pathway - drug effects; β-Catenin
• ISSN: 1535-7163; 1538-8514
• DOI: 10.1158/1535-7163.MCT-16-0585

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 produces antitumor 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. .