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

Sci Rep. 2016 May 20;6:26142. doi: 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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Zebrafish

Substances

  • 2-O-benzylinositol 1,3,4,5,6-pentakisphosphate
  • Antineoplastic Agents
  • Enzyme Inhibitors
  • Inositol Phosphates
  • PDK1 protein, human
  • Pyruvate Dehydrogenase Acetyl-Transferring Kinase
  • Protein-Serine-Threonine Kinases
  • Phospholipase C gamma