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A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion
Claudio Raimondi, Veronique Calleja, Riccardo Ferro, Alessandro Fantin, Andrew M Riley, Barry V L Potter, Caroline H Brennan, Tania Maffucci, Banafshé Larijani, Marco Falasca
OAI: oai:purehost.bath.ac.uk:publications/2729e205-bb23-4670-945e-be1da1b03678 • DOI: https://doi.org/10.1038/srep26142
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- 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 1,3,4,5,6-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.
PDK1 inhibitor, 2-O-benzyl-myo-inositol 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.
Animals Antineoplastic Agents/pharmacology Breast Neoplasms/drug therapy Cell Line Cell Movement/drug effects Disease Models Animal Enzyme Inhibitors/pharmacology Heterografts Humans Inositol Phosphates/pharmacology Melanoma/drug therapy Neoplasm Transplantation Phospholipase C gamma/antagonists & inhibitors Protein Binding Protein Multimerization Protein-Serine-Threonine Kinases/antagonists & inhibitors Zebrafish /dk/atira/pure/sustainabledevelopmentgoals/good_health_and_well_being name=SDG 3 - Good Health and Well-being