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Title: Regulation of WNT/Beta-catenin pathway in the disease progression of osteosarcoma
Keywords: Wnt/beta-catenin signaling; osteosarcoma; Wnt-targeted therapeutics; small molecule inhibitors; curcumin; SFRPs
Issue Date: 13-Aug-2010
Citation: LEOW PAY CHIN (2010-08-13). Regulation of WNT/Beta-catenin pathway in the disease progression of osteosarcoma. ScholarBank@NUS Repository.
Abstract: Osteosarcoma is an aggressive bone malignancy with a poorly understood molecular etiology. Recent evidence has implicated the canonical Wnt/ß-catenin signaling pathway and this study is aimed at developing novel Wnt-targeted therapies for osteosarcoma treatment. The first part of our study describes the evaluation of several natural occurring compounds, such as curcumin and PKF118-310, and the elucidation of their mechanism of action as Wnt antagonists in osteosarcoma. To achieve greater potency, curcumin was further functionalized and a structure-activity-relationship analysis of 43 analogues suggested that conformation restriction around the central linker dienone moiety between the terminal phenyl rings, as well as the introduction of suitable alkoxyl and hydroxyl group substitutions on the aromatic rings of curcumin structure, were useful approaches. In addition, we investigated the functional role of endogenous secreted Wnt antagonists, SFRP1, 2, 4 and 5, and found that they differentially suppressed anchorage-dependent growth, colony formation efficiency, invasion and migration in osteosarcoma. Anti-tumor activities were mediated through down-regulations of MMP-2, cyclin D1, c-Myc and survivin. Lastly, using the Human Wnt Signaling Pathway RT2 ProfilerTM PCR array, we identified additional Wnt target genes such as WISP1, Brachyury, SLC9A3R1 and JUN that might play a significant role in regulating osteosarcoma tumorigenesis and metastasis with over-expressions of SFRP2 or SFRP5 or treatment with curcumin analogue 3-3 in U2OS cells. All in all, our findings not only provided deeper insights into the contributory role of aberrant canonical Wnt/ß-catenin signaling in osteosarcoma disease progression, but also a greater understanding of the potential of small molecules and SFRPs as Wnt antagonists in osteosarcoma. These knowledge may be useful for the subsequent discovery and development of novel targeted therapy for osteosarcoma.
Appears in Collections:Ph.D Theses (Open)

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