Strong evidence suggests that phospholipase C gamma 1 (PLC gamma 1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLC gamma 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 gamma 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-InsP(5)), could affect PDK1/PLC gamma 1 interaction and impair PLC gamma 1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP(5) interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLC gamma 1 complex. 2-O-Bn-InsP(5) is able to inhibit the epidermal growth factor-induced PLC gamma 1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP(5) inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLC gamma 1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP(5) as a leading compound for development of anti-metastatic drugs.
A Small Molecule Inhibitor of PDK1/PLC gamma 1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion / C. Raimondi, V. Calleja, R. Ferro, A. Fantin, A. Riley, B. Potter, C. Brennan, T. Maffucci, B. Larijani, M. Falasca. - In: SCIENTIFIC REPORTS. - ISSN 2045-2322. - 6(2016), pp. 26142.1-26142.14. [10.1038/srep26142]
A Small Molecule Inhibitor of PDK1/PLC gamma 1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion
A. Fantin;
2016
Abstract
Strong evidence suggests that phospholipase C gamma 1 (PLC gamma 1) is a suitable target to counteract tumourigenesis and metastasis dissemination. We recently identified a novel signalling pathway required for PLC gamma 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 gamma 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-InsP(5)), could affect PDK1/PLC gamma 1 interaction and impair PLC gamma 1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP(5) interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLC gamma 1 complex. 2-O-Bn-InsP(5) is able to inhibit the epidermal growth factor-induced PLC gamma 1 phosphorylation and activity, ultimately resulting in impaired cancer cell migration and invasion. Importantly, we report that 2-O-Bn-InsP(5) inhibits cancer cell dissemination in zebrafish xenotransplants. This work demonstrates that the PDK1/PLC gamma 1 complex is a potential therapeutic target to prevent metastasis and it identifies 2-O-Bn-InsP(5) as a leading compound for development of anti-metastatic drugs.File | Dimensione | Formato | |
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