Abstract
Simple SummaryGrowing evidence suggests that Wnt signaling may be crucial for tumorigenesis and progression of soft tissue sarcomas (STS). Inhibitors of this pathway are currently in clinical trials or pre-clinical studies in order to validate its utility in different neoplasia. One of this inhibitors, PRI-724, is showing promising results for advanced pancreatic adenocarcinoma or ovarian cancer. We found that PRI-724 is able to suppress cell viability/proliferation and to increase cell death rates of soft tissue sarcomas cells in vitro. CDC25A, a target gene of Wnt signaling pathway, is essential for STS proliferation because its downregulation via siRNA was able to mimic the effect of PRT-724 on cell cycle arrest and evaluation of NCBI/GenBank data confirmed its overexpression in STS patients’ samples. Moreover, in vitro administration of PRI-724 along with standard STS chemotherapeutic drugs improved the efficacy of chemotherapy, suggesting that Wnt inhibition could be a promising new therapeutic strategy in STS.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.
Highlights
Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumors of mesenchymal origin with 50 different histological subtypes
Our findings show that inhibition of CBP/β-catenin interaction suppresses the proliferation of a wide range of soft tissue sarcomas (STS) cell lines and patient-derived cells and promotes cell death, at least in part, via CDC25A downregulation
To test the effect of CBP/β-catenin disruption on cell proliferation, STS cell lines and primary cultures representing different sarcoma histologies and mutational background were exposed to increasing concentrations of PRI-724 (0.1–50 μM) for 24, 48 and 72 h (Table S1)
Summary
Soft tissue sarcomas (STS) are a heterogeneous group of malignant tumors of mesenchymal origin with 50 different histological subtypes. STS are part of the so-called rare cancers, since they have a low incidence on the population, representing only one per cent of all solid malignant neoplasia in adults [1,2]. Surgery with or without radiotherapy and chemotherapy is the first treatment option in patients with localized disease. Recurrence is frequent, reaching up to 60% or higher in high-risk localized populations. Systematic therapy for metastatic or unresectable patients is needed to offer some disease control [3]. The therapeutic options for inoperable or metastatic STS only offer a limited benefit on the prognosis and patients’ survival making the search for new molecular targets and the development of novel therapeutic approaches a still unmatched goal
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