Impact of wnt/β-catenin inhibition on cell proliferation through cdc25a downregulation in soft tissue sarcomas

Abstract

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 thatWnt 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 ofWnt/ 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 latterwas critical because its downregulation via siRNAwas able tomimic the effectofPRI-724oncell cycle arrest andcelldeathinduction. An evaluation of NCBI/GenBank data confirmed that CDC25AmRNAis elevated in STS patients. Importantly, PRI-724 in combination with standard STS chemotherapeutics doxorubicin or trabectedin enhanced their antitumoral effect in a synergisticmanner according to isobolographic analysis, suggesting thatWnt inhibition through PRI-724 could be a beneficial combination regime in patients with advanced STS.