Reversing the Warburg Effect as a Treatment for Glioblastoma

Poteet, Ethan; Choudhury, Gourav Roy; Winters, Ali; Li, Wenjun; Ryou, Myoung-Gwi; Liu, Ran; Tang, Lin; Ghorpade, Anuja; Yi, Wen; Yuan, Fang; Keir, Stephen T.; Yan, Hai; Bigner, Darell D.; Simpkins, James W.; Yang, Shaohua

doi:10.1074/jbc.m112.440354

Cited by 87 publications

(93 citation statements)

References 49 publications

(53 reference statements)

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“…Metabolic analysis was performed by NMR analysis of culture medium and cell extracts. The culture media were supplemented with [1][2][3][4][5][6][7][8][9][10][11][12][13] C]glucose to monitor rates of lactate production by the appearance of [3][4][5][6][7][8][9][10][11][12][13] C]lactate in the culture medium, and of Krebs cycle flux by analysis of 13 C labeling patterns of glutamate from the cell extract. H-NMR spectra of cell culture media and cell methanol/water (80%/20%; v/v) extracts were acquired on a 600-MHz NMR Spectrometer (Varian-Agilent Technologies, Santa Clara, CA, USA), using a 3-mm indirect detection probe.…”

Section: Methodsmentioning

confidence: 99%

“…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. 9 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. 10 Given the mitochondrial involvement in stemness and differentiation, 11 one can ask whether manipulation of mitochondrial physiology results in an improvement of therapy efficacy.…”

mentioning

confidence: 99%

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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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Section: Methodsmentioning

confidence: 99%

mentioning

confidence: 99%

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

et al. 2014

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“…AMPK phosphorylates also the C-terminal residue of another CKI, p27 Kip1 , causing its stabilization (Figure 2) 135 . Likewise, methylene blue (MB)-mediated activation of AMPK reduces expression of cyclins A2, B1 and D1, leading to proliferative arrest 136 . Moreover, activation of AMPK due to mitochondrial dysfunction promotes p53-dependent transcription of the F-box protein archipelago.…”

Section: Pkm2mentioning

confidence: 99%

Two-way communication between the metabolic and cell cycle machineries: the molecular basis

2015

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The relationship between cellular metabolism and the cell cycle machinery is by no means unidirectional. The ability of a cell to enter the cell cycle critically depends on the availability of metabolites. Conversely, the cell cycle machinery commits to regulating metabolic networks in order to support cell survival and proliferation. In this review, we will give an account of how the cell cycle machinery and metabolism are interconnected. Acquiring information on how communication takes place among metabolic signaling networks and the cell cycle controllers is crucial to increase our understanding of the deregulation thereof in disease, including cancer.

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“…Other articles have also indicated that TMZ resistance is associated with the expression of vascular endothelial growth factor (VEGF) 12 and epidermal growth factor receptor (EGFR) 13 . Changes in EGFR expression by itself activates both MEK and PI3 kinase pathways 14,15 .…”

Section: Introductionmentioning

confidence: 99%

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

Yao

Zhang

et al. 2015

Cell Mol Immunol

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Although temozolomide (TMZ) is the first-line chemotherapeutic agent for glioblastoma, it is often non-curative due to drug resistance. To overcome the resistance of glioblastoma cells to TMZ, it is imperative to identify prognostic markers for outcome prediction and to develop chemo-sensitizing agents. Here, the gene expression profiles of TMZ-resistant and TMZ-sensitive samples were compared by microarray analysis, and mitogen-activated protein kinase kinase 2 (MEK2) was upregulated specifically in resistant glioma cells but not in sensitive tumor cells or non-tumor tissues. Moreover, a comprehensive analysis of patient data revealed that the increased level of MEK2 expression correlated well with the advancement of glioma grade and worse prognosis in response to TMZ treatment. Furthermore, reducing the level of MEK2 in U251 glioma cell lines or xenografted glioma models through shRNA-mediated gene knockdown inhibited cell proliferation and enhanced the sensitivity of cells toward TMZ treatment. Further analysis of tumor samples from glioma patients by real-time PCR indicated that an increased MEK2 expression level was closely associated with the activation of many drug resistance genes. Finally, these resistance genes were downregulated after MEK2 was silenced in vitro, suggesting that the mechanism of MEK2-induced chemo-resistance could be mediated by the transcriptional activation of these resistance genes. Collectively, our data indicated that the expression level of MEK2 could serve as a prognostic marker for glioma chemotherapy and that MEK2 antagonists can be used as chemo-sensitizers to enhance the treatment efficacy of TMZ.

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Reversing the Warburg Effect as a Treatment for Glioblastoma

Cited by 87 publications

References 49 publications

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

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

Two-way communication between the metabolic and cell cycle machineries: the molecular basis

MEK2 is a prognostic marker and potential chemo-sensitizing target for glioma patients undergoing temozolomide treatment

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