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

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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.
Original languageEnglish
Article number26142
JournalScientific Reports
Volume6
DOIs
Publication statusPublished - 20 May 2016

Keywords

  • 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

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    Raimondi, C., Calleja, V., Ferro, R., Fantin, A., Riley, A. M., Potter, B. V. L., Brennan, C. H., Maffucci, T., Larijani, B., & Falasca, M. (2016). A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. Scientific Reports, 6, [26142]. https://doi.org/10.1038/srep26142