title: Dual blocking of mTor and PI3K elicits a prodifferentiation effect on glioblastoma stem-like cells.
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.
authors.affiliation: Department of Molecular Cancer Science, Yamagata University School of Medicine, Yamagata, Japan.
authors.forename: Jun
authors.initials: J
authors.lastname: Sunayama
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
authors.forename: Ken-ichiro
authors.initials: K
authors.lastname: Matsuda
authors.forename: Ken
authors.initials: K
authors.lastname: Tachibana
authors.forename: Kaori
authors.initials: K
authors.lastname: Suzuki
authors.forename: Yoshitaka
authors.initials: Y
authors.lastname: Narita
authors.forename: Soichiro
authors.initials: S
authors.lastname: Shibui
authors.forename: Kaori
authors.initials: K
authors.lastname: Sakurada
authors.forename: Takamasa
authors.initials: T
authors.lastname: Kayama
authors.forename: Arata
authors.initials: A
authors.lastname: Tomiyama
authors.forename: Chifumi
authors.initials: C
authors.lastname: Kitanaka
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation / Q000187:drug effects; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002867:Chromones / Q000494:pharmacology; D004359:Drug Therapy, Combination; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009025:Morpholines / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000473:pathology*; D058539:Phosphatidylinositol 3-Kinase / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D011804:Quinolines / Q000494:pharmacology*; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D002867:Chromones; D004791:Enzyme Inhibitors; D007093:Imidazoles; D007166:Immunosuppressive Agents; D009025:Morpholines; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; C546842:MTOR protein, human; D058539:Phosphatidylinositol 3-Kinase; D051057:Proto-Oncogene Proteins c-akt; D058570:TOR Serine-Threonine Kinases; C531198:dactolisib; D020123:Sirolimus