期刊
CANCER LETTERS
卷 414, 期 -, 页码 1-15出版社
ELSEVIER IRELAND LTD
DOI: 10.1016/j.canlet.2017.11.004
关键词
Cancer stem-like cells; Osteosarcoma; Wnt/beta-catenin signaling; Apoptosis; IWR-1; Doxorubicin
类别
资金
- Portuguese Foundation for Science and Technology (FCT) through COMPETE
- QREN
- FEDER [Pest-C/SAU/UI3282]
- FCT [UID/NEU/04539/2013]
- COMPETE [POCI-01-0145-FEDER-007440, SFRH/BD/69603/2010]
- Nucleo Regional do Centro da Liga Portuguesa Contra o Cancro/CIMAGO (Bolsas de Investigacao em Oncologia NRC-LPCC/CIMAGO)
- Fundação para a Ciência e a Tecnologia [SFRH/BD/69603/2010] Funding Source: FCT
Wnt/beta-catenin or canonical Wnt signaling pathway regulates the self-renewal of cancer stem-like cells (CSCs) and is involved in tumor progression and chemotherapy resistance. Previously, we reported that this pathway is activated in a subset of osteosarcoma CSCs and that doxorubicin induced stemness properties in differentiated cells through Wnt/beta-catenin activation. Here, we investigated whether pharmacological Wnt/beta-catenin inhibition, using a tankyrase inhibitor (IWR-1), might constitute a strategy to target CSCs and improve chemotherapy efficacy in osteosarcoma. IWR-1 was specifically cytotoxic for osteosarcoma CSCs. IWR-1 impaired spheres' self-renewal capacity by compromising landmark steps of the canonical Wnt signaling, namely translocation of beta-catenin to the nucleus and subsequent TCF/LEF activation and expression of Wnt/beta-catenin downstream targets. IWR-1 also hampered the activity and expression of key stemness-related markers. In vitro, IWR-1 induced apoptosis of osteosarcoma spheres and combined with doxorubicin elicited synergistic cytotoxicity, reversing spheres' resistance to this drug. In vivo, IWR-1 co-administration with doxorubicin substantially decreased tumor progression, associated with specific down-regulation of TCF/LEF transcriptional activity, nuclear beta-catenin and expression of the putative CSC marker Sox2. We suggest that targeting the Wnt/beta-catenin pathway can eliminate CSCs populations in osteosarcoma. Combining conventional chemotherapy with Wnt/beta-catenin inhibition may ameliorate therapeutic outcomes, by eradicating the aggressive osteosarcoma CSCs and reducing drug resistance. (c) 2017 Elsevier B.V. All rights reserved.
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