Tp53-induced Glycolysis and Apoptosis Regulator (TIGAR) Protects Glioma Cells from Starvation-induced Cell Death by Up-regulating Respiration and Improving Cellular Redox Homeostasis

Wanka, Christina; Steinbach, Joachim P.; Rieger, Johannes

doi:10.1074/jbc.m112.384578

Cited by 146 publications

(159 citation statements)

References 67 publications

(71 reference statements)

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“…A significant decrease of ATP levels accompanied by unaltered glucose concentrations in the tumor tissue of bevacizumab-treated mice could indicate that glucose levels in the tumor are insufficient to sustain ATP production. One reason might be a lack of oxygen leading to less efficient ATP generation by suppressed oxidative phosporylation and therefore increased glucose needs (5,7,38). Microdialysis analyses have shown a correlation between systemic glucose concentrations and glucose levels within the glioma tissue (11).…”

Section: Discussionmentioning

confidence: 99%

“…There is also evidence of increased glycolysis in glioblastoma. First, malignant gliomas are characterized by activation of growth factor receptor/PI3 kinase/Akt signaling (2) leading to increased reliance on glycolysis (3) and by loss of p53 wild-type activity which can result in reduced expression of synthesis of cytochrome C oxidase 2 (SCO2), necessary for the proper assembly and function of the mitochondrial respiratory chain (4,5), and of tp53-induced glycolysis and apoptosis regular (TIGAR), which suppresses glycolysis (6,7). Second, hypoxia typically present in malignant glioma is expected to stimulate accumulation of HIF-1α and subsequent expression of genes involved in glucose metabolism and in the suppression of oxidative phosphorylation (8,9).…”

Section: Introductionmentioning

confidence: 99%

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ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

Rieger

Bähr

Maurer

et al. 2014

International Journal of Oncology

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Abstract. Limiting dietary carbohydrates inhibits glioma growth in preclinical models. Therefore, the ERGO trial (NCT00575146) examined feasibility of a ketogenic diet in 20 patients with recurrent glioblastoma. Patients were put on a low-carbohydrate, ketogenic diet containing plant oils. Feasibility was the primary endpoint, secondary endpoints included the percentage of patients reaching urinary ketosis, progression-free survival (PFS) and overall survival. The effects of a ketogenic diet alone or in combination with bevacizumab was also explored in an orthotopic U87MG glioblastoma model in nude mice. Three patients (15%) discontinued the diet for poor tolerability. No serious adverse events attributed to the diet were observed. Urine ketosis was achieved at least once in 12 of 13 (92%) evaluable patients. One patient achieved a minor response and two patients had stable disease after 6 weeks. Median PFS of all patients was 5 (range, 3-13) weeks, median survival from enrollment was 32 weeks. The trial allowed to continue the diet beyond progression. Six of 7 (86%) patients treated with bevacizumab and diet experienced an objective response, and median PFS on bevacizumab was 20.1 (range, 12-124) weeks, for a PFS at 6 months of 43%. In the mouse glioma model, ketogenic diet alone had no effect on median survival, but increased that of bevacizumab-treated mice from 52 to 58 days (p<0.05).In conclusion, a ketogenic diet is feasible and safe but probably has no significant clinical activity when used as single agent in recurrent glioma. Further clinical trials are necessary to clarify whether calorie restriction or the combination with other therapeutic modalities, such as radiotherapy or anti-angiogenic treatments, could enhance the efficacy of the ketogenic diet.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

Rieger

Bähr

Maurer

et al. 2014

International Journal of Oncology

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“…TIGAR has been demonstrated to act as a negative regulator of glycolysis by lowering intracellular levels of fructose-2,6-bisphosphate, leading to the pentose phosphate pathway (PPP) activation and NADPH production (16). TIGAR was also found to protect glioma cells from hypoxia-and ROS-induced cell death by stimulating mitochondrial energy metabolism and oxygen consumption in a p53/TP53-independent manner (19). A recent report showed that TIGAR has a dual role in cancer cell survival through inhibiting both apoptosis and autophagy in response to tumor chemotherapy (20).…”

Section: Introductionmentioning

confidence: 96%

“…Although TIGAR has been reported to function in the control of redox status in several cell types (15,19), its role in mammalian oocytes remains unknown. Moreover, to date, few factor(s) were identified to induce the oxidative stress in HFD oocytes.…”

Section: Comparative Proteomic Analysis Of Ovulated Oocytes From Contmentioning

confidence: 99%

Loss of TIGAR Induces Oxidative Stress and Meiotic Defects in Oocytes from Obese Mice

Wang

Cheng

et al. 2018

Molecular & Cellular Proteomics

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SummaryMaternal obesity has been reported to impair oocyte quality in mice, however, the underlying mechanisms remain unclear. In the present study, by conducting a comparative proteomic analysis, we identified a reduced expression of TIGAR protein in ovulated oocytes from high-fat diet (HFD)-fed mice. Specific depletion of TIGAR in mouse oocytes results in the marked elevation of reactive oxygen species (ROS) levels and the failure of meiotic apparatus assembly. Importantly, forced expression of TIGAR in HFD oocytes not only attenuates ROS production, but also partly prevents spindle disorganization and chromosome misalignment during meiosis. Meantime, we noted that TIGAR knockdown in oocytes induces a strong activation of autophagy, while overexpression of TIGAR significantly reduces the LC3 accumulation in HFD oocytes. By anti-oxidant treatment, we further demonstrated that such an autophagic response is dependent on the TIGAR-controlled ROS production. In summary, our data indicate a role for TIGAR in modulating redox homeostasis during oocyte maturation, and uncover that loss of TIGAR is a critical pathway mediating the effects of maternal obesity on oocyte quality.

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“…p53 is activated by metabolic stress, in part through AMP-activated protein kinase (AMPK) (Vousden and Ryan, 2009;Zhang et al, 2010), which increases in anoxic turtle white muscle (Rider et al, 2009). In addition, a recent study of the p53 target Tp53-induced glycolysis and apoptosis regulator (TIGAR) showed that activation reduced the generation of reactive oxygen species (ROS) and elevated levels of reduced glutathione (Wanka et al, 2012). Because the downregulation of energy pathways and protection against cell death and oxidative stress are hallmarks of anoxia tolerance, it is not surprising to find evidence of p53 activation in the turtle (Zhang et al, 2013).…”

Section: Neuroprotection At the Molecular Levelmentioning

confidence: 99%

Cellular Basis for Learning Impairment in Fragile X Syndrome

Larson¹

2014

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Public reporting burden for this collection of information is estimated to average 1 hour per response, including the time for reviewing instructions, searching existing data sources, gathering and maintaining the data needed, and completing and reviewing this collection of information. Send comments regarding this burden estimate or any other aspect of this collection of information, including suggestions for reducing this burden to Department of Defense, Washington Headquarters Services, Directorate for Information , 1215 Jefferson Davis Highway, Suite 1204, Arlington, VA 22202-4302. Respondents should be aware that notwithstanding any other provision of law, no person shall be subject to any penalty for failing to comply with a collection of information if it does not display a currently valid OMB control number. PLEASE DO NOT RETURN YOUR FORM TO THE ABOVE ADDRESS. REPORT DATE August 2014 REPORT TYPE PERFORMING ORGANIZATION NAME(S) AND ADDRESS(ES)University of Illinois at Chicago PERFORMING ORGANIZATION REPORT NUMBERChicago, IL 60612-4305 SPONSORING / MONITORING AGENCY NAME(S) AND ADDRESS(ES) 10. SPONSOR/MONITOR'S ACRONYM(S) U.S. Army Medical Research and Materiel Command Fort Detrick, Maryland 21702-5012 SPONSOR/MONITOR'S REPORT NUMBER(S) DISTRIBUTION / AVAILABILITY STATEMENTApproved for Public Release; Distribution Unlimited SUPPLEMENTARY NOTES ABSTRACTThis research combines behavioral, electrophysiological, and molecular approaches to elucidate the cellular basis for learning impairment in Fragile X Syndrome (FXS), using olfactory learning in Fmr1-KO mice as a model system. We hypothesize that FMRP, the protein missing in FXS, participates in two aspects of circuit function that are critical to learning: synaptic plasticity and the generation and survival of new neurons in the adult brain. Efforts in the second year of support were directed toward establishing a method to specifically upregulate neurogenesis in adult fragile X mice, test fragile X mice for learning deficits in hippocampal-independent tasks, and determine if learning affects NMDA receptor trafficking to synapses. Significant advances have been made in the establishment of behavioral paradigms to test both hippocampal -dependent and -independent forms of olfactory learning. Experimental paradigms have also been refined for the study of neurogenesis in the olfactory bulb, glutamate receptor expression as it relates to olfactory learning in olfactory cortex and hippocampus, and the effects of aging on glutamate receptor expression. These studies are likely to advance our understanding of intellectual disability and autism in addition to the specific condition of fragile X syndrome. This knowledge will be necessary for the development of rational strategies for prevention and treatment of cognitive impairments from a variety of causes. SUBJECT TERMSFragile X Syndrome, synaptic plasticity, long-term potentiation, glutamate receptors, neurogenesis, olfactory learning INTRODUCTIONFragile X syndrome is the most common inherited form of intellect...

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Tp53-induced Glycolysis and Apoptosis Regulator (TIGAR) Protects Glioma Cells from Starvation-induced Cell Death by Up-regulating Respiration and Improving Cellular Redox Homeostasis

Cited by 146 publications

References 67 publications

ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

ERGO: A pilot study of ketogenic diet in recurrent glioblastoma

Loss of TIGAR Induces Oxidative Stress and Meiotic Defects in Oocytes from Obese Mice

Cellular Basis for Learning Impairment in Fragile X Syndrome

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