Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Wilson, X.; Gosa, Laura; Daniëls, Veerle W.; Ta, Lisa; Tsang, Jonathan; Higgins, Brian; Gilmore, William B.; Bayley, Nicholas; Harati, Mitra Dehghan; Lee, Jason T.; Yong, William H.; Kornblum, Harley I.; Bensinger, Steven J.; Mischel, Paul S.; Rao, P. Nagesh; Clark, Peter M.; Cloughesy, Timothy F.; Letaï, Anthony; Nathanson, David

doi:10.1038/nm.4418

Cited by 88 publications

(68 citation statements)

References 53 publications

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“…Large-scale, shRNA library screening identified that the inhibition of MYC , P38MAPK , or ERK signaling pathways may be synthetically lethal with PI3K inhibitor PX-866 ( Kim et al, 2011 ). EGFR inhibition is synthetically lethal with pharmacological stabilization of P53 ( Mai et al, 2017 ). P53 mutations have also sensitized GBM cells to combined p-AKT inhibition and radiation by antagonizing DNA repair ( Palanichamy et al, 2018 ).…”

Section: Emerging Targets In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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Glioblastoma multiforme (GBM), the most common and aggressive primary brain tumor, has a high mortality rate despite extensive efforts to develop new treatments. GBM exhibits both intra- and intertumor heterogeneity, lending to resistance and eventual tumor recurrence. Large-scale genomic and proteomic analysis of GBM tumors has uncovered potential drug targets. Effective and “druggable” targets must be validated to embark on a robust medicinal chemistry campaign culminating in the discovery of clinical candidates. Here, we review recent developments in GBM drug discovery and delivery. To identify GBM drug targets, we performed extensive bioinformatics analysis using data from The Cancer Genome Atlas project. We discovered 20 genes, BOC, CLEC4GP1, ELOVL6, EREG, ESR2, FDCSP, FURIN, FUT8-AS1, GZMB, IRX3, LITAF, NDEL1, NKX3-1, PODNL1, PTPRN, QSOX1, SEMA4F, TH, VEGFC, and C20orf166AS1 that are overexpressed in a subpopulation of GBM patients and correlate with poor survival outcomes. Importantly, nine of these genes exhibit higher expression in GBM versus low-grade glioma and may be involved in disease progression. In this review, we discuss these proteins in the context of GBM disease progression. We also conducted computational multi-parameter optimization to assess the blood-brain barrier (BBB) permeability of small molecules in clinical trials for GBM treatment. Drug delivery in the context of GBM is particularly challenging because the BBB hinders small molecule transport. Therefore, we discuss novel drug delivery methods, including nanoparticles and prodrugs. Given the aggressive nature of GBM and the complexity of targeting the central nervous system, effective treatment options are a major unmet medical need. Identification and validation of biomarkers and drug targets associated with GBM disease progression present an exciting opportunity to improve treatment of this devastating disease.

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Section: Emerging Targets In Glioblastomamentioning

confidence: 99%

Current Challenges and Opportunities in Treating Glioblastoma

et al. 2018

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“…Separate tumour cell lines have been found to respond differently to metabolism-altering compounds, with some eliciting heightened responses, due to their endogenous levels of hypoxia-induced factor 1-alpha (22). The PTEN status of cell lines has been shown to affect metabolic activity (23) as well as p53 (24). Potentially due to their mutant p53 alleles (25), the primarily glycolytic lines U251 and T98G have been shown to be unable to properly activate AMPK signalling (26) which is critical for survival in a hypoxic environment (27).…”

Section: Discussionmentioning

confidence: 99%

The suitability of glioblastoma cell lines as models for primary glioblastoma cell metabolism

Arthurs

Keating

Conn

2020

Preprint

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Background In contrast to most non-malignant cells, cells comprising Glioblastoma multiforme (GBM), a deadly brain tumour with extremely poor prognosis, preferentially utilise glycolysis over oxidative phosphorylation for metabolism in a phenomenon known as the ‘Warburg effect’. As effective treatments for GBM are severely lacking, research into therapeutics targeting the disease’s highly glycolytic state offer a promising avenue to improve patient survival. These studies often employ GBM cell lines for in vitro studies which translate poorly to the in vivo patient context. Methods The metabolic traits of the seven most commonly used GBM cell lines were assessed using a Seahorse Bioscience Metabolic Flux Analyser and compared to primary GBM cells and primary healthy mixed neural cells from the same patients. Results In support of the glycolytic nature of the patient-derived GBM cell lines, basal mitochondrial rate (p = 0.043) and ATP-linked respiration (p < 0.001) were significantly lower than primary adjacent normal cells from the same patient and reserve capacity (p = 0.037) and Krebs Cycle capacity (p = 0.002) were significantly higher for 12 patients. While no cell line was found to accurately replicate all metabolic attributes of primary GBM cells, specific parameters could be modelled by specific lines. Conclusions U251MG, U373MG and D54 lines are recommended for researching mitochondrial metabolism, and the D645 line for researching ATP-linked respiration. The T98G cell line recapitulated glycolysis-related metabolic parameters of the primary GBM cells and is recommended for research relating to glycolysis. These findings can guide preclinical research into the development of novel therapeutics targeting metabolic pathways in GBM.

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“…Following activation, it participates in various cellular processes such as cell senescence, apoptosis, DNA damage repair, cell cycle, antioxidative stress, energy metabolism regulation, tumor generation, and other physiological and pathological processes [38][39][40]. P53 plays a vital role in the apoptotic signaling pathways, including membrane apoptotic signaling and mitochondrial apoptotic pathways, and affects the transcription and expression of many apoptosis-related cytokines in the nucleus [41]. SIRT1 reduces the transcriptional activity of p53, and blocks p53-dependent cell apoptosis caused by DNA damage [42].…”

Section: Discussionmentioning

confidence: 99%

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

Zhou

Qiao

Liu

et al. 2020

Preprint

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Background Mesenchymal stem cells (MSCs) represent a promising treatment option for acute kidney injury (AKI).The main drawbacks of MSC therapy including the lack of specific homing following systemic infusion and early death of the cells in the inflammatory microenvironment, directly affect the therapeutic efficacy of MSCs. Erythropoietin (EPO)-preconditioning promotes the therapeutic effect of the MSCs, although the underlying mechanism remains unknown. In this study, we sought to investigate the efficacy and mechanism of EPO on bone marrow mesenchymal stem cells (BMSCs) for the treatment of AKI. ResultsWe found that incubation of BMSCs with ischemia/reperfusion(I/R)-induced AKI kidney homogenate supernatant (KHS) caused apoptosis in the BMSCs, which was decreased following EPO pretreatment indicating that EPO protected the cells from apoptosis. Further, we found that EPO upregulated SIRT1 and Bcl-2 expression, and downregulated p53 expression. The EPO-mediated antiapoptotic mechanism in pretreated BMSCs may be mediated though the SIRT1 pathway. In a rat AKI model, our data showed that 24 h following intravenous infusion, GFP-BMSCs were predominantly in the lungs. However, EPO pretreatment reduced the lung entrapment of BMSCs, and increased the distribution of the BMSCs to the target organs. AKI rats infused with EPO-BMSCs had significantly lower levels of serum IL-1β and TNF-a and significantly higher level of IL-10 compared to rats infused with BMSCs. The administration of EPO-BMSCs after reperfusion was more effective in reducing serum creatinine, blood urea nitrogen, and pathological scores in the I/R-AKI rats than BMSCs.Conclusions Our data suggest that EPO pretreatment enhances the efficacy of BMSCs in improving renal function and pathological presentation in I/R-AKI rats. BackgroundAcute kidney injury (AKI) is one of the most clinically impactful diseases with high morbidity and mortality [1,2]. Multiple injuries such as those resulting from sepsis, ischemia/reperfusion (I/R), and drug administration may induce AKI. I/R injury is a major cause of human AKI, which is associated with tubular necrosis, cast formation, tubular dilation, loss of brush border, and inflammation [3]. AKI remains a worldwide public health concern due to the increased risk for subsequent development of 4 chronic kidney disease (CKD) [4]. The annual medical expenses associated with AKI treatment places a heavy burden on the public health care system, and yet AKI lacks an established treatment strategy. Therefore, there is an urgent need to find innovative and effective therapeutic strategies for AKI. The application of mesenchymal stem cells (MSCs) has been suggested as a potentially promising treatment strategy for AKI [5,6].In the recent years, MSCs have become an area of intense research in the field of stem cell therapy.MSCs are adherent, fibroblast-like cells, derived from different tissues and organs including bone marrow, umbilical cord blood, adipose tissue, and solid organs that have the potential for multidirectional diff...

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Cytoplasmic p53 couples oncogene-driven glucose metabolism to apoptosis and is a therapeutic target in glioblastoma

Cited by 88 publications

References 53 publications

Current Challenges and Opportunities in Treating Glioblastoma

Current Challenges and Opportunities in Treating Glioblastoma

The suitability of glioblastoma cell lines as models for primary glioblastoma cell metabolism

Bone mesenchymal stem cells pretreated with erythropoietin accelerate the repair of acute kidney injury

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