論文 - 詳細
| RRC ID | 12296 |
|---|---|
| 著者 | Sunayama J, Sato A, Matsuda K, Tachibana K, Watanabe E, Seino S, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C. |
| タイトル | FoxO3a functions as a key integrator of cellular signals that control glioblastoma stem-like cell differentiation and tumorigenicity. |
| ジャーナル | Stem Cells |
| Abstract |
Glioblastoma is one of the most aggressive types of human cancer, with invariable and fatal recurrence even after multimodal intervention, for which cancer stem-like cells (CSLCs) are now being held responsible. Our recent findings indicated that combinational inhibition of phosphoinositide-3-kinase/Akt/mammalian target of rapamycin (mTOR) and mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK)/extracellular signal-regulated kinase (ERK) pathways effectively promotes the commitment of glioblastoma CSLCs to differentiation and thereby suppresses their tumorigenicity. However, the mechanism by which these two signaling pathways are coordinated to regulate differentiation and tumorigenicity remains unknown. Here, we identified FoxO3a, a common phosphorylation target for Akt and ERK, as a key transcription factor that integrates the signals from these pathways. Combinational blockade of both the pathways caused nuclear accumulation and activation of FoxO3a more efficiently than blockade of either alone, and promoted differentiation of glioblastoma CSLCs in a FoxO3a expression-dependent manner. Furthermore, the expression of a constitutively active FoxO3a mutant lacking phosphorylation sites for both Akt and ERK was sufficient to induce differentiation and reduce tumorigenicity of glioblastoma CSLCs. These findings suggest that FoxO3a may play a pivotal role in the control of differentiation and tumorigenicity of glioblastoma CSLCs by the PI3K/Akt/mTOR and MEK/ERK signaling pathways, and also imply that developing methods targeting effective FoxO3a activation could be a potential approach to the treatment of glioblastoma. |
| 巻・号 | 29(9) |
| ページ | 1327-37 |
| 公開日 | 2011-9-1 |
| DOI | 10.1002/stem.696 |
| PMID | 21793107 |
| MeSH | Animals Brain Neoplasms / metabolism* Brain Neoplasms / pathology* Cell Differentiation / physiology Female Forkhead Box Protein O3 Forkhead Transcription Factors / biosynthesis Forkhead Transcription Factors / metabolism* Glioblastoma / metabolism* Glioblastoma / pathology* Humans MAP Kinase Signaling System / drug effects Male Mice Mice, Inbred BALB C Mice, Nude Mitogen-Activated Protein Kinases / metabolism Neoplastic Stem Cells / metabolism* Neoplastic Stem Cells / pathology* Phosphatidylinositol 3-Kinases / metabolism Phosphoinositide-3 Kinase Inhibitors Proto-Oncogene Proteins c-akt / antagonists & inhibitors Proto-Oncogene Proteins c-akt / metabolism Signal Transduction TOR Serine-Threonine Kinases / antagonists & inhibitors TOR Serine-Threonine Kinases / metabolism Tumor Cells, Cultured Up-Regulation |
| IF | 6.022 |
| 引用数 | 62 |
| WOS 分野 | BIOTECHNOLOGY & APPLIED MICROBIOLOGY ONCOLOGY HEMATOLOGY CELL & TISSUE ENGINEERING CELL BIOLOGY |
| オルトメトリクス指標 |
オルトメトリクス指標項目
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| 最多言及媒体 | X(Twitter) |
| 各媒体での言及数の合計 | 2 |
| 過去6か月間でのオルトメトリクス指標の変動値 | 0.0 |
| リソース情報 | |
| ヒト・動物細胞 | A172(RCB2530) |