title: FoxO proteins or loss of functional p53 maintain stemness of glioblastoma stem cells and survival after ionizing radiation plus PI3K/mTOR inhibition.
abstract: Dual PI3K/mTOR inhibitors do not effectively radiosensitize glioblastoma multiforme stem cells (GBM-SCs), but p53-proficient GBM-SCs are more responsive than p53-deficient ones. Here, we found that p53-proficient, but not p53-deficient, GBM-SCs lost stemness and differentiated after γ-irradiation combined with PI3K/mTOR inhibition; expression of FoxO proteins was also lost. FoxO overexpression inhibited the loss of stem cell markers under these conditions. Combined, but not single, FoxO1/3 deletion or pharmacological inhibition of FoxO transcriptional activity strongly reduced stem and progenitor marker expression, particularly that of Sox2. Binding of FoxO1 and FoxO3 to the sox2 regulatory regions was also found. However, combined FoxO1/3 knockdown strongly reduced self-renewal and post-treatment survival only in p53-proficient GBM-SCs. This suggests that FoxO1 and FoxO3 are crucial for functional stemness and post-treatment survival mainly in p53-proficient but not in p53-deficient GBM-SCs, and that these functions can be maintained through the loss of DNA damage-responsive p53 instead.
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.
authors.forename: Elke
authors.initials: E
authors.lastname: Firat
authors.affiliation: Department of Radiation Oncology, University Hospital Freiburg, Freiburg, Germany.|German Cancer Consortium (DKTK), Freiburg, Germany.|German Cancer Research Center (DKFZ), Heidelberg, Germany.
authors.forename: Gabriele
authors.initials: G
authors.lastname: Niedermann
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics / Q000528:radiation effects; D000071161:Forkhead Box Protein O1 / Q000235:genetics / Q000378:metabolism*; D000071316:Forkhead Box Protein O3 / Q000235:genetics / Q000378:metabolism*; D005909:Glioblastoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism* / Q000528:radiation effects; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines / Q000494:pharmacology; D034622:RNA Interference; D011839:Radiation, Ionizing; D058570:TOR Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D000071161:Forkhead Box Protein O1; D000071316:Forkhead Box Protein O3; D007093:Imidazoles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D011804:Quinolines; D058570:TOR Serine-Threonine Kinases; D016159:Tumor Suppressor Protein p53; C085126:FOXO1 protein, human; C499517:FOXO3 protein, human; C546842:MTOR protein, human; C531198:dactolisib
keywords: FOXO; cancer stem cells; glioblastoma; p53; radiotherapy