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A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion
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 prot...
Autores principales: | , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2016
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873738/ https://www.ncbi.nlm.nih.gov/pubmed/27199173 http://dx.doi.org/10.1038/srep26142 |
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author | Raimondi, Claudio Calleja, Veronique Ferro, Riccardo Fantin, Alessandro Riley, Andrew M. Potter, Barry V. L. Brennan, Caroline H. Maffucci, Tania Larijani, Banafshé Falasca, Marco |
author_facet | Raimondi, Claudio Calleja, Veronique Ferro, Riccardo Fantin, Alessandro Riley, Andrew M. Potter, Barry V. L. Brennan, Caroline H. Maffucci, Tania Larijani, Banafshé Falasca, Marco |
author_sort | Raimondi, Claudio |
collection | PubMed |
description | 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-InsP(5)), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP(5) interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP(5) 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-InsP(5) 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-InsP(5) as a leading compound for development of anti-metastatic drugs. |
format | Online Article Text |
id | pubmed-4873738 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2016 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-48737382016-06-02 A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion Raimondi, Claudio Calleja, Veronique Ferro, Riccardo Fantin, Alessandro Riley, Andrew M. Potter, Barry V. L. Brennan, Caroline H. Maffucci, Tania Larijani, Banafshé Falasca, Marco Sci Rep Article 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-InsP(5)), could affect PDK1/PLCγ1 interaction and impair PLCγ1-dependent cellular functions in cancer cells. Here, we demonstrate that 2-O-Bn-InsP(5) interacts specifically with the pleckstrin homology domain of PDK1 and impairs formation of a PDK1/PLCγ1 complex. 2-O-Bn-InsP(5) 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-InsP(5) 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-InsP(5) as a leading compound for development of anti-metastatic drugs. Nature Publishing Group 2016-05-20 /pmc/articles/PMC4873738/ /pubmed/27199173 http://dx.doi.org/10.1038/srep26142 Text en Copyright © 2016, Macmillan Publishers Limited http://creativecommons.org/licenses/by/4.0/ This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ |
spellingShingle | Article Raimondi, Claudio Calleja, Veronique Ferro, Riccardo Fantin, Alessandro Riley, Andrew M. Potter, Barry V. L. Brennan, Caroline H. Maffucci, Tania Larijani, Banafshé Falasca, Marco A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title | A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title_full | A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title_fullStr | A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title_full_unstemmed | A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title_short | A Small Molecule Inhibitor of PDK1/PLCγ1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion |
title_sort | small molecule inhibitor of pdk1/plcγ1 interaction blocks breast and melanoma cancer cell invasion |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4873738/ https://www.ncbi.nlm.nih.gov/pubmed/27199173 http://dx.doi.org/10.1038/srep26142 |
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