title: A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion.
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.
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Inositide Signalling Group, London E1 2AT, UK.
authors.forename: Claudio
authors.initials: C
authors.lastname: Raimondi
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, Lincoln's Inn Fields Laboratories, London Research Institute, London WC2A 3LY, UK.
authors.forename: Veronique
authors.initials: V
authors.lastname: Calleja
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Inositide Signalling Group, London E1 2AT, UK.
authors.forename: Riccardo
authors.initials: R
authors.lastname: Ferro
authors.affiliation: UCL Institute of Ophthalmology, University College London, London EC1V 9EL, UK.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fantin
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.
authors.forename: Andrew M
authors.initials: AM
authors.lastname: Riley
authors.affiliation: Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Bath BA2 7AY, UK.|Department of Pharmacology, University of Oxford, Mansfield Road, Oxford OX1 3QT.
authors.forename: Barry V L
authors.initials: BV
authors.lastname: Potter
authors.affiliation: Queen Mary University of London, School of Biological and Chemical Sciences, London E1 4NS, UK.
authors.forename: Caroline H
authors.initials: CH
authors.lastname: Brennan
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Inositide Signalling Group, London E1 2AT, UK.
authors.forename: Tania
authors.initials: T
authors.lastname: Maffucci
authors.affiliation: Cell Biophysics Laboratory, Cancer Research UK, Lincoln's Inn Fields Laboratories, London Research Institute, London WC2A 3LY, UK.
authors.forename: Banafshé
authors.initials: B
authors.lastname: Larijani
authors.affiliation: Queen Mary University of London, Barts and The London School of Medicine and Dentistry, Blizard Institute, Inositide Signalling Group, London E1 2AT, UK.|Metabolic Signalling Group, School of Biomedical Sciences, Curtin Health Innovation Research Institute, Curtin University, Perth, Western Australia 6102, Australia.
authors.forename: Marco
authors.initials: M
authors.lastname: Falasca
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000188:drug therapy; D002460:Cell Line; D002465:Cell Movement / Q000187:drug effects; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D064593:Heterografts; D006801:Humans; D007295:Inositol Phosphates / Q000494:pharmacology*; D008545:Melanoma / Q000188:drug therapy; D009368:Neoplasm Transplantation; D051966:Phospholipase C gamma / Q000037:antagonists & inhibitors*; D011485:Protein Binding; D055503:Protein Multimerization; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors*; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D015027:Zebrafish
chemical_list: C546965:2-O-benzylinositol 1,3,4,5,6-pentakisphosphate; D000970:Antineoplastic Agents; D004791:Enzyme Inhibitors; D007295:Inositol Phosphates; C000631429:PDK1 protein, human; D000081382:Pyruvate Dehydrogenase Acetyl-Transferring Kinase; D017346:Protein Serine-Threonine Kinases; D051966:Phospholipase C gamma