A Small Molecule Inhibitor of PDK1/PLCy1 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-phosphoinositidedependent prote...
| Main Authors: | , , , , , , , , , |
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| Format: | Journal Article |
| Published: |
Nature Publishing Group
2016
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| Online Access: | http://hdl.handle.net/20.500.11937/45537 |
| _version_ | 1848757313405452288 |
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| author | Raimondi, C. Calleja, V. Ferro, R. Fantin, A. Riley, A. Potter, B. Brennan, C. Maffucci, T. Larijani, B. Falasca, Marco |
| author_facet | Raimondi, C. Calleja, V. Ferro, R. Fantin, A. Riley, A. Potter, B. Brennan, C. Maffucci, T. Larijani, B. Falasca, Marco |
| author_sort | Raimondi, C. |
| building | Curtin Institutional Repository |
| collection | Online Access |
| 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-phosphoinositidedependent 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-myoinositol 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. |
| first_indexed | 2025-11-14T09:26:07Z |
| format | Journal Article |
| id | curtin-20.500.11937-45537 |
| institution | Curtin University Malaysia |
| institution_category | Local University |
| last_indexed | 2025-11-14T09:26:07Z |
| publishDate | 2016 |
| publisher | Nature Publishing Group |
| recordtype | eprints |
| repository_type | Digital Repository |
| spelling | curtin-20.500.11937-455372017-09-13T14:22:14Z A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. Raimondi, C. Calleja, V. Ferro, R. Fantin, A. Riley, A. Potter, B. Brennan, C. Maffucci, T. Larijani, B. Falasca, Marco 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-phosphoinositidedependent 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-myoinositol 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. 2016 Journal Article http://hdl.handle.net/20.500.11937/45537 10.1038/srep26142 Nature Publishing Group unknown |
| spellingShingle | Raimondi, C. Calleja, V. Ferro, R. Fantin, A. Riley, A. Potter, B. Brennan, C. Maffucci, T. Larijani, B. Falasca, Marco A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title | A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title_full | A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title_fullStr | A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title_full_unstemmed | A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title_short | A Small Molecule Inhibitor of PDK1/PLCy1 Interaction Blocks Breast and Melanoma Cancer Cell Invasion. |
| title_sort | small molecule inhibitor of pdk1/plcy1 interaction blocks breast and melanoma cancer cell invasion. |
| url | http://hdl.handle.net/20.500.11937/45537 |