title: Crosstalk between the PI3K/mTOR and MEK/ERK pathways involved in the maintenance of self-renewal and tumorigenicity of glioblastoma stem-like cells.
abstract: The molecular signaling pathways orchestrating the biology of cancer stem-like cells (CSLCs), including glioblastoma, remain to be elucidated. We investigated in this study the role of the MEK/extracellular signal-regulated kinase (ERK) pathway in the control of self-renewal and tumorigenicity of glioblastoma CSLCs, particularly in relation to the PI3K/mTOR (mammalian target of rapamycin) pathway. Targeted inactivation of MEK alone using pharmacological inhibitors or siRNAs resulted in reduced sphere formation of both cell line- and patient-derived glioblastoma CSLCs, accompanied by their differentiation into neuronal and glial lineages. Interestingly, this effect of MEK inactivation was apparently augmented in the presence of NVP-BEZ235, a dual inhibitor of PI3K and mTOR. As a potential explanation for this observed synergy, we found that inactivation of either the MEK/ERK or PI3K/mTOR pathway triggered activation of the other, suggesting that there may be mutually inhibitory crosstalk between these two pathways. Significantly, inactivation of either pathway led to the reduced activation of p70S6K, and siRNA-mediated knockdown of p70S6K resulted in the activation of both pathways, which no longer maintained the cross-inhibitory relationship. Finally, combinational blockade of both pathways in glioblastoma CSLCs suppressed their tumorigenicity, whether transplanted subcutaneously or intracranially, more efficiently than blockade of either alone. Our findings suggest that there is p70S6K-mediated, cross-inhibitory regulation between the MEK/ERK and PI3K/mTOR pathways, in which each contribute to the maintenance of the self-renewal and tumorigenic capacity of glioblastoma CSLCs. Thus, combinational disruption of these pathways would be a rational and effective strategy in the treatment of 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: Ken-Ichiro
authors.initials: K
authors.lastname: Matsuda
authors.forename: Atsushi
authors.initials: A
authors.lastname: Sato
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: D000607:Aminoacetonitrile / Q000031:analogs & derivatives / Q000494:pharmacology; D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects / Q000235:genetics; D045744:Cell Line, Tumor; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D005909:Glioblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D020929:Mitogen-Activated Protein Kinase Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009570:Nitriles / Q000494:pharmacology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D014407:Tumor Cells, Cultured
chemical_list: D000607:Aminoacetonitrile; D002070:Butadienes; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D007093:Imidazoles; D020929:Mitogen-Activated Protein Kinase Kinases; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; C424127:SL 327; C113580:U 0126; C531198:dactolisib