Comparison of Spheroids Formed by Rat Glioma Stem Cells and Neural Stem Cells Reveals Differences in Glucose Metabolism and Promising Therapeutic Applications

Morfouace, Marie; Lalier, Lisenn; Bahut, Muriel; Bonnamain, Virginie; Naveilhan, Philippe; Guette, Catherine; Oliver, Lisa; Guéguen, Naïg; Reynier, Pascal; Vallette, François M.

doi:10.1074/jbc.m111.320028

Cited by 60 publications

(60 citation statements)

References 46 publications

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“…Cancer stem cells (CSCs), defined in vivo as tumorinitiating cells (TICs), or, for solid tumors, as cells capable of 3D tumorsphere growth in vitro, often have increased glycolytic metabolism compared to more differentiated tumor cells [66][67][68][69]. Glioma stem cells have been reported to be less glycolytic than differentiated glioma cells, as exceptions to this rule [70].…”

Section: Cancer Stem Cellsmentioning

confidence: 99%

Mitochondrial functions in stem cells

Margineantu

Hockenbery

2016

Current Opinion in Genetics & Development

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Section: Cancer Stem Cellsmentioning

confidence: 99%

Mitochondrial functions in stem cells

Margineantu

Hockenbery

2016

Current Opinion in Genetics & Development

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“…Dichloroacetate also forces rat glioma CSCs into OXPHOS but without triggering apoptosis. 47 Intriguingly, the resistant and high-glycolytic P19SCs showed an overexpression of both enzymes involved in the mechanism of action of dichloroacetate (PDH and PDK), which are probably deregulated in SCs reducing substrate availability to enter the Krebs cycle.…”

mentioning

confidence: 99%

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

et al. 2014

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The relationship between mitochondrial metabolism and cell viability and differentiation in stem cells (SCs) remains poorly understood. In the present study, we compared mitochondrial physiology and metabolism between P19SCs before/after differentiation and present a unique fingerprint of the association between mitochondrial activity, cell differentiation and stemness. In comparison with their differentiated counterparts, pluripotency of P19SCs was correlated with a strong glycolytic profile and decreased mitochondrial biogenesis and complexity: round, low-polarized and inactive mitochondria with a closed permeability transition pore. This decreased mitochondrial capacity increased their resistance against dichloroacetate. Thus, stimulation of mitochondrial function by growing P19SCs in glutamine/pyruvate-containing medium reduced their glycolytic phenotype, induced loss of pluripotent potential, compromised differentiation and became P19SCs sensitive to dichloroacetate. Because of the central role of this type of SCs in teratocarcinoma development, our findings highlight the importance of mitochondrial metabolism in stemness, proliferation, differentiation and chemoresistance. In addition, the present work suggests the regulation of mitochondrial metabolism as a tool for inducing cell differentiation in stem line therapies. Embryonal carcinoma cells, including the P19 cell line, are pluripotent cancer stem cells (CSCs) derived from pluripotent germ cell tumors called teratocarcinomas. These have been described as the malignant counterparts of embryonic stem cells (ESCs) and are considered a good model to study stem cell (SC) differentiation. The P19 cell line can be maintained as undifferentiated cells (P19SCs) or differentiated (P19dCs) to any cell type of the three germ layers. Similar to ESCs, P19 cells differentiate with retinoic acid (RA) in a dose-dependent manner and depending on growth conditions. 1 Although differentiation generally yields a mixed population of differentiated cells, P19 cells grown in monolayer and treated with 1 mM RA primarily differentiate in endoderm or mesoderm, while retaining their immortality. 2,3Although some therapeutic approaches for regenerative medicine and to targeting CSCs are based on differentiation 4 and mitochondrial-targeted therapies, 5,6 very little is known about the role of mitochondrial metabolism in SC maintenance and differentiation.7 Several mitochondrial characteristics that distinguish transformed cells from healthy cells have been described, 8 including increased mitochondrial transmembrane electric potential (Dcm), which may result from decreased mitochondrial ATP production under normoxia. Similarly, normal SCs primarily rely on glycolysis for energy supply, although the exact mechanism how this occurs in the presence of oxygen and the relationship between SC metabolism and cell fate control is not yet completely understood. 10Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physi...

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“…In HMCLs, 2-DG treatment increased steady-state levels of O 2 •− in both stem-like and bulk tumor cells. Pharmacological manipulation of glucose metabolism (using dichloroacetate that inhibits pyruvate dehydrogenase kinase) has been shown to incur specific cytotoxicity on glioma stem cells and not normal neural stem cells [92]. Biochemically, 2-DG blocks pyruvate production by glycolysis and partially inhibits the pentose phosphate pathway, reducing NADPH regeneration by 50% and increasing cellular oxidative stress in cancer cells [99, 100].…”

Section: Discussionmentioning

confidence: 99%

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

et al. 2016

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Therapeutic advances have markedly prolonged overall survival in multiple myeloma (MM) but the disease currently remains incurable. In a panel of MM cell lines (MM.1S, OPM-2, H929, and U266), using CD138 immunophenotyping, side population staining, and stem cell-related gene expression, we demonstrate the presence of stem-like tumor cells. Hypoxic culture conditions further increased CD138low stem-like cells with upregulated expression of OCT4 and NANOG. Compared to MM cells, these stem-like cells maintained lower steady-state pro-oxidant levels with increased uptake of the fluorescent deoxyglucose analog. In primary human MM samples, increased glycolytic gene expression correlated with poorer overall and event-free survival outcomes. Notably, stem-like cells showed increased mitochondrial mass, rhodamine 123 accumulation, and orthodox mitochondrial configuration while more condensed mitochondria were noted in the CD138high cells. Glycolytic inhibitor 2-deoxyglucose (2-DG) induced ER stress as detected by qPCR (BiP, ATF4) and immunoblotting (BiP, CHOP) and increased dihydroethidium probe oxidation both CD138low and CD138high cells. Treatment with a mitochondrial-targeting agent decyl-triphenylphosphonium (10-TPP) increased intracellular steady-state pro-oxidant levels in stem-like and mature MM cells. Furthermore, 10-TPP mediated increases in mitochondrial oxidant production were suppressed by ectopic expression of manganese superoxide dismutase. Relative to 2-DG or 10-TPP alone, 2-DG plus 10-TPP combination showed increased caspase 3 activation in MM cells with minimal toxicity to the normal hematopoietic progenitor cells. Notably, treatment with polyethylene glycol conjugated catalase significantly reduced 2-DG and/or 10-TPP-induced apoptosis of MM cells. Also, the combination of 2-DG with 10-TPP decreased clonogenic survival of MM cells. Taken together, this study provides a novel strategy of metabolic oxidative stress-induced cytotoxicity of MM cells via 2-DG and 10-TPP combination therapy.

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Comparison of Spheroids Formed by Rat Glioma Stem Cells and Neural Stem Cells Reveals Differences in Glucose Metabolism and Promising Therapeutic Applications

Cited by 60 publications

References 46 publications

Mitochondrial functions in stem cells

Mitochondrial functions in stem cells

Mitochondrial metabolism directs stemness and differentiation in P19 embryonal carcinoma stem cells

Mitochondrial-Targeted Decyl-Triphenylphosphonium Enhances 2-Deoxy-D-Glucose Mediated Oxidative Stress and Clonogenic Killing of Multiple Myeloma Cells

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