RRC ID 19232
Author Sunayama J, Sato A, Matsuda K, Tachibana K, Suzuki K, Narita Y, Shibui S, Sakurada K, Kayama T, Tomiyama A, Kitanaka C.
Title Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells.
Journal Neuro-oncology
Abstract 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.
Volume 12(12)
Pages 1205-19
Published 2010-12
DOI 10.1093/neuonc/noq103
PII noq103
PMID 20861085
PMC PMC3018946
MeSH Animals Blotting, Western Cell Differentiation / drug effects Cell Line, Tumor Cell Proliferation / drug effects Chromones / pharmacology Drug Therapy, Combination Enzyme Inhibitors / pharmacology Glioblastoma / drug therapy Glioblastoma / metabolism Glioblastoma / pathology* Humans Imidazoles / pharmacology* Immunosuppressive Agents / pharmacology Male Mice Mice, Inbred BALB C Mice, Nude Morpholines / pharmacology Neoplastic Stem Cells / pathology* Phosphatidylinositol 3-Kinase / antagonists & inhibitors* Phosphatidylinositol 3-Kinase / metabolism Proto-Oncogene Proteins c-akt / metabolism Quinolines / pharmacology* Signal Transduction Sirolimus / pharmacology TOR Serine-Threonine Kinases / antagonists & inhibitors* TOR Serine-Threonine Kinases / genetics TOR Serine-Threonine Kinases / metabolism Xenograft Model Antitumor Assays
IF 10.091
Times Cited 49
Human and Animal Cells A172 (RCB2530)