PUBLICATION
A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion
- Authors
- Raimondi, C., Calleja, V., Ferro, R., Fantin, A., Riley, A.M., Potter, B.V., Brennan, C.H., Maffucci, T., Larijani, B., Falasca, M.
- ID
- ZDB-PUB-160521-7
- Date
- 2016
- Source
- Scientific Reports 6: 26142 (Journal)
- Registered Authors
- Brennan, Caroline
- Keywords
- Metastasis, Pharmacology
- 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*
- Zebrafish
- PubMed
- 27199173 Full text @ Sci. Rep.
Citation
Raimondi, C., Calleja, V., Ferro, R., Fantin, A., Riley, A.M., Potter, B.V., 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.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping