title: FOXO3a orchestrates glioma cell responses to starvation conditions and promotes hypoxia-induced cell death.
abstract: Forkhead box O (FOXO) transcription factors are homeostatic regulators adjusting diverse cellular processes crucial for metabolism and survival. In gliomas, FOXOs have been shown to modulate cell death, proliferation and differentiation. Here, we investigated the role of FOXO3a in human malignant gliomas with special regard to starvation conditions. Expression of FOXO3a increased with WHO grade and was accentuated in the perinecrotic niche, colocalizing with hypoxia‑inducible factor 1α (HIF1α) expression. FOXO3a was upregulated in hypoxia and translocation of FOXO3a from the cytoplasm to the nucleus was induced by serum starvation, pharmacological inhibition of protein kinase B (PKB) and hypoxia. Overexpression of FOXO3a induced tumor necrosis factor‑related apoptosis‑inducing ligand (TRAIL) expression and resulted in spontaneous cell death. Knockdown of FOXO3a (shFOXO3a), on the one hand, enhanced the sensitivity of glioma cells towards H2O2 under normoxia. On the other hand, it decreased consumption of glucose and oxygen, resulting in improved survival during glucose and oxygen deprivation. Mechanistically, in shFOXO3a cells, hypoxia‑response element reporter activity, as well as the expression of common HIF1α target genes, was increased, suggesting disinhibited HIF1α signaling. However, glucose transporter 1 (GLUT1) expression was inversely regulated, and this may have been caused by an upregulation of TP53 in shFOXO3a cells. These data reveal a novel role of FOXO3a‑dependent gene regulation in the complex adaptive responses of gliomas towards starvation signals. Strategies that target FOXO3a function may directly or indirectly alter glioma cell behavior and viability in the hypoxic niche.
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Daniel P
authors.initials: DP
authors.lastname: Brucker
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Gabriele D
authors.initials: GD
authors.lastname: Maurer
authors.affiliation: Institute of Neurology (Edinger Institute), Goethe University Hospital, Frankfurt, Germany.
authors.forename: Patrick N
authors.initials: PN
authors.lastname: Harter
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Johannes
authors.initials: J
authors.lastname: Rieger
authors.affiliation: Dr. Senckenberg Institute of Neurooncology, Goethe University Hospital, Frankfurt, Germany.
authors.forename: Joachim P
authors.initials: JP
authors.lastname: Steinbach
mesh_terms: D017209:Apoptosis; D001921:Brain / Q000378:metabolism / Q000473:pathology; D015687:Cell Hypoxia / Q000235:genetics*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000235:genetics; D002470:Cell Survival / Q000235:genetics; D000071316:Forkhead Box Protein O3 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D005910:Glioma / Q000235:genetics / Q000473:pathology*; D005947:Glucose / Q000378:metabolism; D051272:Glucose Transporter Type 1 / Q000096:biosynthesis*; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis / Q000235:genetics; D018384:Oxidative Stress / Q000235:genetics; D010101:Oxygen Consumption; D034622:RNA Interference; D034741:RNA, Small Interfering / Q000235:genetics; D012097:Repressor Proteins / Q000378:metabolism; D015398:Signal Transduction; D013482:Superoxide Dismutase / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000096:biosynthesis; D015534:Trans-Activators / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis* / Q000235:genetics
chemical_list: C486381:CITED2 protein, human; C499517:FOXO3 protein, human; D000071316:Forkhead Box Protein O3; D051272:Glucose Transporter Type 1; C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D034741:RNA, Small Interfering; D012097:Repressor Proteins; C495677:SLC2A1 protein, human; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; C495901:TP53 protein, human; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; D006861:Hydrogen Peroxide; D013482:Superoxide Dismutase; D005947:Glucose