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SOST Inhibits Prostate Cancer Invasion [electronic resource].

Published
Washington, D.C. : United States. Dept. of Energy, 2015.
Oak Ridge, Tenn. : Distributed by the Office of Scientific and Technical Information, U.S. Dept. of Energy
Physical Description
Article numbers e0,142,058 : digital, PDF file
Additional Creators
Lawrence Berkeley National Laboratory, United States. Department of Energy, National Institutes of Health (U.S.), and United States. Department of Energy. Office of Scientific and Technical Information
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Summary
Inhibitors of Wnt signaling have been shown to be involved in prostate cancer (PC) metastasis; however the role of Sclerostin (Sost) has not yet been explored. Here we show that elevated Wnt signaling derived from Sost deficient osteoblasts promotes PC invasion, while rhSOST has an inhibitory effect. In contrast, rhDKK1 promotes PC elongation and filopodia formation, morphological changes characteristic of an invasive phenotype. Furthermore, rhDKK1 was found to activate canonical Wnt signaling in PC3 cells, suggesting that SOST and DKK1 have opposing roles on Wnt signaling in this context. Gene expression analysis of PC3 cells co-cultured with OBs exhibiting varying amounts of Wnt signaling identified CRIM1 as one of the transcripts upregulated under highly invasive conditions. We found CRIM1 overexpression to also promote cell-invasion. These findings suggest that bone-derived Wnt signaling may enhance PC tropism by promoting CRIM1 expression and facilitating cancer cell invasion and adhesion to bone. We concluded that SOST and DKK1 have opposing effects on PC3 cell invasion and that bone-derived Wnt signaling positively contributes to the invasive phenotypes of PC3 cells by activating CRIM1 expression and facilitating PC-OB physical interaction. As such, we investigated the effects of high concentrations of SOST in vivo. In conclusion, we found that PC3-cells overexpressing SOST injected via the tail vein in NSG mice did not readily metastasize, and those injected intrafemorally had significantly reduced osteolysis, suggesting that targeting the molecular bone environment may influence bone metastatic prognosis in clinical settings.
Report Numbers
E 1.99:1259524
Subject(s)
Note
Published through SciTech Connect.
11/06/2015.
PLoS ONE 10 11 ISSN 1932-6203 AM
Bryan D. Hudson; Nicholas R. Hum; Cynthia B. Thomas; Ayano Kohlgruber; Aimy Sebastian; Nicole M. Collette; Matthew A. Coleman; Blaine A. Christiansen; Gabriela G. Loots.
Funding Information
LDRD-10-ERD-020
DK07573
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