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A Small Molecule Inhibitor of PDK1/PLC?1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.

ABSTRACT: Strong evidence suggests that phospholipase C?1 (PLC?1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLC?1 activation which involves formation of a protein complex with 3-phosphoinositide-dependent protein kinase 1 (PDK1). In an effort to define novel strategies to inhibit PLC?1-dependent signals we tested here whether a newly identified and highly specific PDK1 inhibitor, 2-O-benzyl-myo-inositol 1,3,4,5,6-pentakisphosphate (2-O-Bn-InsP5), could affect PDK1/PLC?1 interaction and impair PLC?1-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/PLC?1 complex. 2-O-Bn-InsP5 is able to inhibit the epidermal growth factor-induced PLC?1 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/PLC?1 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.

SUBMITTER: Raimondi C

PROVIDER: S-EPMC4873738 | biostudies-literature | 2016 May

REPOSITORIES: biostudies-literature

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A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.

Raimondi Claudio C Calleja Veronique V Ferro Riccardo R Fantin Alessandro A Riley Andrew M AM Potter Barry V L BV Brennan Caroline H CH Maffucci Tania T Larijani Banafshé B Falasca Marco M

Scientific reports 20160520

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-phosphoinositide-dependent 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-myo-inositol 1, ...[more]

PMID: 27199173

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Dataset Information

A Small Molecule Inhibitor of PDK1/PLC?1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.

Publications

A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.

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