Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells
| Autor: | Jun Sunayama, Kenichiro Matsuda, Kaori Suzuki, Atsushi Sato, Arata Tomiyama, Kaori Sakurada, Ken Tachibana, Chifumi Kitanaka, Soichiro Shibui, Yoshitaka Narita, Takamasa Kayama |
|---|---|
| Rok vydání: | 2010 |
| Předmět: |
Male
Cancer Research Morpholines Cellular differentiation Blotting Western Mice Nude Biology Mice chemistry.chemical_compound Cell Line Tumor medicine Animals Humans LY294002 Enzyme Inhibitors PI3K/AKT/mTOR pathway Cell Proliferation Phosphoinositide-3 Kinase Inhibitors Sirolimus Mice Inbred BALB C Gene knockdown Cell growth TOR Serine-Threonine Kinases Imidazoles Cell Differentiation Xenograft Model Antitumor Assays Molecular biology Neural stem cell Oncology chemistry Chromones Basic and Translational Investigations Neoplastic Stem Cells Quinolines Cancer research Drug Therapy Combination Neurology (clinical) Phosphatidylinositol 3-Kinase Signal transduction Glioblastoma Proto-Oncogene Proteins c-akt Immunosuppressive Agents Signal Transduction medicine.drug |
| Zdroj: | Neuro-Oncology. 12:1205-1219 |
| ISSN: | 1523-5866 1522-8517 |
| DOI: | 10.1093/neuonc/noq103 |
| Popis: | Glioblastoma, the most intractable cerebral tumor, is highly lethal. Recent studies suggest that cancer stem-like cells (CSLCs) have the capacity to repopulate tumors and mediate radio- and chemoresistance, implying that future therapies may need to turn from the elimination of rapidly dividing, but differentiated, tumor cells to specifically targeting the minority of tumor cells that repopulate the tumor. However, the mechanism by which glioblastoma CSLCs maintain their immature stem-like state or, alternatively, become committed to differentiation is poorly understood. Here, we show that the inactivation of mammalian target of rapamycin (mTor) by the mTor inhibitor rapamycin or knockdown of mTor reduced sphere formation and the expression of neural stem cell (NSC)/progenitor markers in CSLCs of the A172 glioblastoma cell line. Interestingly, combination treatment with rapamycin and LY294002, a phosphatidylinositol 3-kinase (PI3K) inhibitor, not only reduced the expression of NSC/progenitor markers more efficiently than single-agent treatment, but also increased the expression of βIII-tubulin, a neuronal differentiation marker. Consistent with these results, a dual PI3K/mTor inhibitor, NVP-BEZ235, elicited a prodifferentiation effect on A172 CSLCs. Moreover, A172 CSLCs, which were induced to undergo differentiation by pretreatment with NVP-BEZ235, exhibited a significant decrease in their tumorigenicity when transplanted either subcutaneously or intracranially. Importantly, similar results were obtained when patient-derived glioblastoma CSLCs were used. These findings suggest that the PI3K/mTor signaling pathway is critical for the maintenance of glioblastoma CSLC properties, and targeting both mTor and PI3K of CSLCs may be an effective therapeutic strategy in glioblastoma. |
| Databáze: | OpenAIRE |
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