Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells.
Binding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH) domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with t...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Public Library of Science (PLoS)
2012-01-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC3485233?pdf=render |
| _version_ | 1818510502125371392 |
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| author | Sangita M Baxi Wei Tan Sean T Murphy Tod Smeal Min-Jean Yin |
| author_facet | Sangita M Baxi Wei Tan Sean T Murphy Tod Smeal Min-Jean Yin |
| author_sort | Sangita M Baxi |
| collection | DOAJ |
| description | Binding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH) domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with the potent and selective PDK1 inhibitor PF-5177624 in the IGF-PI3K pathway blocks breast cancer cell proliferation and transformation. Breast cancer cell lines MCF7 and T47D, representing the luminal ER positive subtype and harboring PIK3CA mutations, were most responsive to IGF-I induction resulting in upregulated AKT and p70S6K phosphorylation via PDK1 activation. PF-5177624 downregulated AKT and p70S6K phosphorylation, blocked cell cycle progression, and decreased cell proliferation and transformation to block IGFR-I induced activation in breast cancer cells. These results may provide insight into clinical strategies for developing an IGFR-I inhibitor and/or a PDK1 inhibitor in luminal breast cancer patients. |
| first_indexed | 2024-12-10T23:20:50Z |
| format | Article |
| id | doaj.art-3c772b7498f8429d9ba7f28053549940 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-10T23:20:50Z |
| publishDate | 2012-01-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-3c772b7498f8429d9ba7f280535499402022-12-22T01:29:43ZengPublic Library of Science (PLoS)PLoS ONE1932-62032012-01-01710e4840210.1371/journal.pone.0048402Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells.Sangita M BaxiWei TanSean T MurphyTod SmealMin-Jean YinBinding of IGF to IGF-IR activates PI3K to generate PIP3 which in turn recruits and activates proteins that contain a pleckstrin homology (PH) domain, including AKT and PDK1. PDK1 is highly expressed in breast tumor samples and breast cancer cell lines. Here we demonstrate that targeting PDK1 with the potent and selective PDK1 inhibitor PF-5177624 in the IGF-PI3K pathway blocks breast cancer cell proliferation and transformation. Breast cancer cell lines MCF7 and T47D, representing the luminal ER positive subtype and harboring PIK3CA mutations, were most responsive to IGF-I induction resulting in upregulated AKT and p70S6K phosphorylation via PDK1 activation. PF-5177624 downregulated AKT and p70S6K phosphorylation, blocked cell cycle progression, and decreased cell proliferation and transformation to block IGFR-I induced activation in breast cancer cells. These results may provide insight into clinical strategies for developing an IGFR-I inhibitor and/or a PDK1 inhibitor in luminal breast cancer patients.http://europepmc.org/articles/PMC3485233?pdf=render |
| spellingShingle | Sangita M Baxi Wei Tan Sean T Murphy Tod Smeal Min-Jean Yin Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. PLoS ONE |
| title | Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. |
| title_full | Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. |
| title_fullStr | Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. |
| title_full_unstemmed | Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. |
| title_short | Targeting 3-phosphoinoside-dependent kinase-1 to inhibit insulin-like growth factor-I induced AKT and p70 S6 kinase activation in breast cancer cells. |
| title_sort | targeting 3 phosphoinoside dependent kinase 1 to inhibit insulin like growth factor i induced akt and p70 s6 kinase activation in breast cancer cells |
| url | http://europepmc.org/articles/PMC3485233?pdf=render |
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