Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade

Tao, Bei; He, Hua; Shi, Xueyin; Wang, Chunlin; Li, Weiqing; Li, Bing; Yan, Dong; Hu, Guohan; Hou, Lingling; Luo, Chun; Chen, Juxiang; Chen, Huairui; Yu, Yuhong; Sun, Qiang; Lu, Yao

doi:10.1016/j.jocn.2012.03.050

Cited by 61 publications

(46 citation statements)

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“…Recently, a number of frequent genetic alterations have been identified in human glioblastoma 16 . Among all of these altered genes, the Ras-Raf-MAP kinase signaling pathway has demonstrated to be important in the control of glioma cell proliferation 17 .…”

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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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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“…9 Various substrates, including glucose, can be converted into fatty acids intracellularly; gliomas express fatty acid synthase (FASN), and expression of this enzyme increases with malignant grade. 10 …”

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confidence: 99%

Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells

et al. 2016

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Background.Glioma is the most common form of primary malignant brain tumor in adults, with approximately 4 cases per 100 000 people each year. Gliomas, like many tumors, are thought to primarily metabolize glucose for energy production; however, the reliance upon glycolysis has recently been called into question. In this study, we aimed to identify the metabolic fuel requirements of human glioma cells.Methods.We used database searches and tissue culture resources to evaluate genotype and protein expression, tracked oxygen consumption rates to study metabolic responses to various substrates, performed histochemical techniques and fluorescence-activated cell sorting-based mitotic profiling to study cellular proliferation rates, and employed an animal model of malignant glioma to evaluate a new therapeutic intervention.Results.We observed the presence of enzymes required for fatty acid oxidation within human glioma tissues. In addition, we demonstrated that this metabolic pathway is a major contributor to aerobic respiration in primary-cultured cells isolated from human glioma and grown under serum-free conditions. Moreover, inhibiting fatty acid oxidation reduces proliferative activity in these primary-cultured cells and prolongs survival in a syngeneic mouse model of malignant glioma.Conclusions.Fatty acid oxidation enzymes are present and active within glioma tissues. Targeting this metabolic pathway reduces energy production and cellular proliferation in glioma cells. The drug etomoxir may provide therapeutic benefit to patients with malignant glioma. In addition, the expression of fatty acid oxidation enzymes may provide prognostic indicators for clinical practice.

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“…Two scenarios may thus result in a decrease in the lipid composition: lipid rich brain tissue replacing less lipid rich tumor cells would decrease the amount of lipids overall while tumor cells would also likely exploit normal physiological pathways related to lipid metabolism in central nervous tissue. There are numerous reports in the literature that fatty acid synthetase (FASN) is highly upregulated in a variety of cancers including GBM and may be a good therapeutic target [29,30]. Future studies will employ more robust methods of lipid identification to confirm the findings of this work, as well as explore the mechanism related to the decrease in lipid composition by examining the metabolic profile and cellular composition of the tumors.…”

Section: Lipid Studies and Decreased Level Of Lipids In Gbmmentioning

confidence: 53%

Lipidomic Analysis of Glioblastoma Multiforme Using Mass Spectrometry

Ha¹,

Showalter²,

Cai³

et al. 2014

CMB

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Glioblastoma multiforme (GBM) is the most common and malignant form of primary brain tumors. It is highly invasive and current treatment options have not improved the survival rate over the past twenty years. Novel approaches and technologies from systems biology have the potential to identify biomarkers that could serve as new therapeutic targets for GBM. This study employed AUTHORS' CONTRIBUTIONSKari Clase was responsible for leading the collaboration, analyzing data and interpreting findings within the context of the biological system and establishing the data collection and sample analysis pipeline. Soo Jung Ha and Gordon M. Showalter conducted the sample preparation, mass spectrometry data collection and statistical data analysis. Jiri Adamec supervised mass spectrometry data collection. John Springer conducted statistical clustering analysis of mass spectrometry data. Shanbao Cai, Haiyan Wang, Wei M. Liu were directly responsible for intellectual input on model set up. They also set up all flank and orthotopic model, mouse monitoring, and isolation of tumor samples. Karen Pollok was responsible regulatory requirements, intellectual input, and all aspects of in vivo model set up, monitoring, and sample collection. Jenna Rickus provided intellectual input. Jann Sarkaria provided tumor cell lines and intellectual input. Aaron Cohen-Gadol provided intellectual input. CONFLICT OF INTERESTThe authors confirm that there is no conflict of interest with the data presented in this article. lipid profiling technology to investigate lipid biomarkers in ectopic and orthotopic human GBM xenograft models. Primary patient cell lines, GBM10 and GBM43, were injected into the flank and the right cerebral hemisphere of NOD/SCID mice. Tumors were harvested from the brain and flank and proteins, metabolites, and lipids extracted from each sample. Reverse phase based high performance liquid chromatography coupled with Fourier transform ion cyclotron resonance mass spectrometry (LC-FTMS) was used to analyze the lipid profiles of tumor samples. Statistical and clustering analyses were performed to detect differences. Over 500 lipids were identified in each tumor model and lipids with the greatest fold effect in the comparison of ectopic versus orthotopic tumor models fell predominantly into four main classes of lipids: glycosphingolipids, glycerophoshpoethanolamines, triradylglycerols, and glycerophosphoserines. Lipidomic analysis revealed differences in glycosphingolipid and triglyceride profiles when the same tumor was propagated in the flank versus the brain. These results underscore the importance of the surrounding physiological environment on tumor development and are consistent with the hypothesis that specific classes of lipids are critical for GBM tumor growth in different anatomical sites. HHS Public Access

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Up-regulation of USP2a and FASN in gliomas correlates strongly with glioma grade

Cited by 61 publications

References 24 publications

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

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

Fatty acid oxidation is required for the respiration and proliferation of malignant glioma cells

Lipidomic Analysis of Glioblastoma Multiforme Using Mass Spectrometry

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