Wnt/β-catenin inhibition attenuates osteosarcoma stemness and chemoresistance

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Wnt/β-catenin inhibition attenuates osteosarcoma stemness and chemoresistance

Monday, 20.11.2017


Sara R. Martins-Neves (a-d), Daniela I. Paiva-Oliveira (a, b), Carlos Fontes-Ribeiro (a, b), Judith V.M.G. Bovée (d), Anne-Marie Cleton-Jansen (d, 1), Célia M.F. Gomes (a, b, c, ∗, 1)

a) Pharmacology and Experimental Therapeutics, IBILI - Faculty of Medicine, University of Coimbra, Coimbra, Azinhaga de Sta. Comba, Celas, 3000-354, Portugal

b) CNC.IBILI, University of Coimbra, Coimbra, Portugal

c) CIMAGO, University of Coimbra, Coimbra, Portugal

d) Department of Pathology, Leiden University Medical Center, P.O.Box 9600, L1-Q, 2300 RC, Leiden, The Netherlands


Wnt/β-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/β-catenin activation. Here, we investigated whether pharmacological Wnt/β-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 β-catenin to the nucleus and subsequent TCF/LEF activation and expression of Wnt/β-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 β-catenin and expression of the putative CSC marker Sox2. We suggest that targeting the Wnt/β-catenin pathway can eliminate CSCs populations in osteosarcoma. Combining conventional chemotherapy with Wnt/β-catenin inhibition may ameliorate therapeutic outcomes, by eradicating the aggressive osteosarcoma CSCs and reducing drug resistance.

Cancer Letters


http://www.sciencedirect.com/science/article/pii/S0304383517306985