Soft tissue sarcomas (STS) are malignant tumours of mesenchymal origin and represent around 1% of adult cancers, being a very heterogeneous group of tumours with more than 50 different subtypes. The Wnt signalling 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 pharmacological inhibition of Wnt signalling 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 in vitro 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.
- Received September 12, 2016.
- Revision received March 2, 2017.
- Accepted March 2, 2017.
- Copyright ©2017, American Association for Cancer Research.