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    Upregulation of RASSF1A in Colon Cancer by Suppression of Angiogenesis Signaling and Akt Activation

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    Author
    Blanchard, T.G.
    Lapidus, R.
    Banerjee, V.
    Date
    2018
    Journal
    Cellular Physiology and Biochemistry
    Publisher
    S. Karger AG
    Type
    Article
    
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    See at
    https://dx.doi.org/10.1159/000492012
    Abstract
    Background/Aims: Silencing of tumor suppressor genes (TSGs) and promotion of angiogenesis are associated with tumor development and metastasis. However, little is known if angiogenic molecules directly control TSGs and vice versa. Methods: A regulatory link between angiogenesis and down regulation of TSGs was evaluated using an anti-cancer agent, andrographolide (AGP) in cancer cells, mouse xenograft tissues and patient derived organoids through gene/protein expression, gene silencing, and immunohistochemical analyses. Results: AGP treatment demonstrated significant expression of RASSF1A and PTEN TSGs in colon cancer and other cancer cells, mouse tissues and organoids. Depletion of RASSF1A with siRNA limited cyclin D1 and BAX expression. SiRNA depletion of PTEN, upstream regulator of RASSF1A resulted in a 50% reduction in RASSF1A expression. Histopathological analysis of the AGP treated tumor sections showed significant reduction in vessel size, microvascular density and tumor mitotic index suggesting suppression of angiogenesis. This was corroborated by protein analysis demonstrating significant reductions in angiogenesis signaling pathway molecules VEGF165, FOXM1, and pAkt, but significant elevation of the endogenous angiogenesis inhibitor Tsp-2. Treatment of cells with exogenous VEGF prevented the suppression of angiogenesis signaling by AGP, resulting in sustained expression of pAkt, an upstream down-regulator of RASSF1A. RASSF1A expression remained low in VEGF treated cells despite the addition of AGP. Conclusion: Our results demonstrate for the first time that AGP induces RASSF1A expression in colon cancer cells and is dependent on angiogenesis signaling events. Therefore, our research may facilitate novel therapeutic options for advanced colon cancer therapy. Copyright 2018 The Author(s). Published by S. Karger AG, Basel.
    Keyword
    Andrographolide (AGP)
    Angiogenesis
    Colon Cancer
    ER stress
    PTEN
    RASSF1A
    Identifier to cite or link to this item
    https://www.scopus.com/inward/record.uri?eid=2-s2.0-85052473932&doi=10.1159%2f000492012&partnerID=40&md5=28570de8c91370b7e7c3d65e6f458e9b; http://hdl.handle.net/10713/9228
    ae974a485f413a2113503eed53cd6c53
    10.1159/000492012
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