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    A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.

    Access Status
    Open access via publisher
    Authors
    Raimondi, C.
    Calleja, V.
    Ferro, R.
    Fantin, A.
    Riley, A.
    Potter, B.
    Brennan, C.
    Maffucci, T.
    Larijani, B.
    Falasca, Marco
    Date
    2016
    Type
    Journal Article
    
    Metadata
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    Citation
    Raimondi, C. and Calleja, V. and Ferro, R. and Fantin, A. and Riley, A. and Potter, B. and Brennan, C. et al. 2016. A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. Scientific Reports. 6: Article 26142.
    Source Title
    Scientific Reports
    DOI
    10.1038/srep26142
    School
    School of Biomedical Sciences
    URI
    http://hdl.handle.net/20.500.11937/45537
    Collection
    • Curtin Research Publications
    Abstract

    Strong evidence suggests that phospholipase Cγ1 (PLCγ1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLCγ1 activation which involves formation of a protein complex with 3-phosphoinositidedependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLCγ1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myoinositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP5 interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLCγ1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP5 inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLCγ1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP5 as a leading compound for development of anti-metastatic drugs.

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