Targeting the Wnt/β-catenin pathway in human osteosarcoma cells
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Fang Fang1, Ashley VanCleave1, Ralph Helmuth1,2, Haydee Torres1,3, Kirby Rickel1,4, Hannah Wollenzien1,5, Hongli Sun6, Erliang Zeng7, Jing Zhao8,9 and Jianning Tao1,3,5,10
1Cancer Biology and Immunotherapies Group, Sanford Research, Sioux Falls, SD, USA
2BRIN Scholar from Dakota Wesleyan University, Sanford Research, Sioux Falls, SD, USA
3Department of Chemistry and Biochemistry, South Dakota State University, Brookings, SD, USA
4Department of Biomedical Engineering, University of South Dakota, Sioux Falls, SD, USA
5Basic Biomedical Sciences, University of South Dakota, Vermillion, SD, USA
6Department of Oral and Maxillofacial Surgery, University of Iowa, Iowa City, IA, USA
7Departments of Preventive & Community Dentistry, Biomedical Engineering, and Biostatistics, Division of Biostatistics and Computational Biology of College of Dentistry, University of Iowa, Iowa City, IA, USA
8Population Health Group, Sanford Research, Sioux Falls, SD, USA
9Department of Internal Medicine, University of South Dakota, Sioux Falls, SD, USA
10Department of Pediatrics, University of South Dakota, Sioux Falls, SD, USA
Jianning Tao, email: [email protected]
Keywords: osteosarcoma; Wnt/β-catenin signaling; PRI-724; Cyclin D1
Received: August 26, 2018 Accepted: November 07, 2018 Published: December 04, 2018
Aberrant activation of Wnt signaling has been implicated in human osteosarcoma, which may provide a genetic vulnerability that can be targeted in osteosarcoma treatment. To test whether Wnt activation is necessary for osteosarcoma growth, colony formation, invasion, and metastasis, we treated human osteosarcoma cells with a small molecule inhibitor of Wnt/β-catenin, PRI-724, which suppresses Wnt/β-catenin-mediated transcription. We found increased protein levels of endogenous active-β-catenin in five human osteosarcoma cell lines. Treatment with PRI-724 was sufficient to inhibit human osteosarcoma 143B and SJSA-1 cell proliferation. Suppressed Wnt signaling was confirmed by decreased protein levels of the Wnt target Cyclin D1. Furthermore, we revealed significant inhibitory effects on cell migration, invasion, and colony formation in the human osteosarcoma cells. Using deposited data from next generation sequencing studies, we analyzed somatic mutations and gene expression of components in the Wnt/β-catenin pathway. We found somatic mutations and upregulated gene expression of many components in the Wnt/ β-catenin pathway, indicating activated Wnt signaling. Taken together, our results illustrate the critical role of Wnt/β-catenin signaling in human osteosarcoma pathogenesis and growth, as well as the therapeutic potential of Wnt inhibitors in the treatment of human osteosarcoma.
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