Mammalian Target of Rapamycin 2 (MTOR2) and C-MYC Modulate Glucosamine-6-Phosphate Synthesis in Glioblastoma (GBM) Cells Through Glutamine: Fructose-6-Phosphate Aminotransferase 1 (GFAT1)

Liu, Bo; Huang, Ziyin; Chen, Xin; See, Yi-Xiang; Chen, Zi-Kai; Yao, Huankai

doi:10.1007/s10571-019-00659-7

Cited by 28 publications

(22 citation statements)

References 51 publications

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“…The transformation of cancer cells from aerobic respiration to glycolysis plays an important role in the occurrence and development of drug resistance. In drug resistant cells and tissues of breast cancer, gastric cancer, glioblastoma, pancreatic adenocarcinoma and non-small cell lung cancer, glycolytic activity increased and reprogramed, and associated metabolic processes changed had been found (Ruprecht et al, 2017;Ye et al, 2017;Zhao et al, 2017;Liu et al, 2019;Sun et al, 2019). In our study, down-regulation of MYCN in NGP cells resulted in a decrease of glycolysis capacity and an increase of basal and maximal respiration; overexpression of MYCN in AS cells induced the increment of glycolysis capacity and decrement of spare respiration capacity.…”

Section: Discussionsupporting

confidence: 51%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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Neuroblastoma (NB) is the most common pediatric malignant extracranial solid tumor. Despite multi-modality therapies, the emergence of drug resistance is an obstacle in the treatment of high-risk NB patients (with MYCN amplification). In our previous study, we found that rapamycin and MK-2206 synergistically induced cell death in MYCN-amplified cell lines but the mechanisms remained unclear. In our present study, either 3-MA or necroatatin-1 blocked the cell death induced by rapamycin and MK-2206, but z-VAD-fmk did not block this cell death. The expressions of autophagy markers (ATG5, ATG7, Beclin-1, LC3 B) and the necroptosis marker RIPK3 increased and another necroptosis marker RIPK1 decreased after the combination treatment of rapamycin and MK-2206, and were accompanied by the morphological characteristics of autophagy and necroptosis. In NB xenograft tumor tissues, the expressions of autophagy and necroptosis markers were consistent with observations in vitro. These data suggested that autophagy and necroptosis contributed to the cell death induced by rapamycin and MK-2206 in NB cells. To understand the role of MYCN in this process, MYCN expression was downregulated in MYCN-amplified cell lines (NGP, BE2) using siRNAs and was upregulated in MYCN non-amplified cell lines (AS, SY5Y) using plasmid. We found the cell death induced by rapamycin and MK-2206 was MYCN-dependent. We also found that the metabolic activity in NB cells was correlated with the expression level of MYCN. This study delineates the role of MYCN in the cell death induced by combination treatment of rapamycin and MK-2206 in MYCN-amplified NB cells.

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Section: Discussionsupporting

confidence: 51%

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

et al. 2020

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“…The connection between glutaminolysis and glycolysis, their dependence on cellular mTOR activity [32] were deeply investigated in many previous glioma studies [31,33]. In addition, both mTOR complexes have been described to play an important role in the regulation of these processes.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

Petővári

Dankó

Krencz

et al. 2019

Pathol. Oncol. Res.

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The high-grade brain malignancy, glioblastoma multiforme (GBM), is one of the most aggressive tumours in central nervous system. The developing resistance against recent therapies and the recurrence rate of GBMs are extremely high. In spite several new ongoing trials, GBM therapies could not significantly increase the survival rate of the patients as significantly. The presence of inter-and intra-tumoral heterogeneity of GBMs arise the problem to find both the pre-existing potential resistant clones and the cellular processes which promote the adaptation mechanisms such as multidrug resistance, stem cell-ness or metabolic alterations, etc. In our work, the in situ metabolic heterogeneity of high-grade human glioblastoma cases were analysed by immunohistochemistry using tissue-microarray. The potential importance of the detected metabolic heterogeneity was tested in three glioma cell lines (grade III-IV) using protein expression analyses (Western blot and WES Simple) and therapeutic drug (temozolomide), metabolic inhibitor treatments (including glutaminase inhibitor) to compare the effects of rapamycin (RAPA) and glutaminase inhibitor combinations in vitro (Alamar Blue and SRB tests). The importance of individual differences and metabolic alterations were observed in mono-therapeutic failures, especially the enhanced Rictor expressions after different monotreatments in correlation to lower sensitivity (temozolomide, doxycycline, etomoxir, BPTES). RAPA combinations with other metabolic inhibitors were the best strategies except for RAPA+glutaminase inhibitor. These observations underline the importance of multi-targeting metabolic pathways. Finally, our data suggest that the detected metabolic heterogeneity (the high mTORC2 complex activity, enhanced expression of Rictor, p-Akt, p-S6, CPT1A, and LDHA enzymes in glioma cases) and the microenvironmental or treatment induced metabolic shift can be potential targets in combination therapy. Therefore, it should be considered to map tissue heterogeneity and alterations with several cellular metabolism markers in biopsy materials after applying recently available or new treatments.

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“…Hence, targeting GFAT1 might exhibit an antitumor effect by reducing HBP activity. Consistent with notion, GFAT1 deficiency impairs the malignant features of glioblastoma (GBM) and reduces the glucosamine-P-6 synthesis [14]. In cholangiocarcinoma, treatment with the GFAT inhibitor DON reduces global O-GlcNAcylated proteins and inhibits cell migration [26].…”

Section: Discussionmentioning

confidence: 62%

“…High GFAT1 expression is identified as an independent predictor of adverse clinical outcome for PDAC patients [12]. Moreover, many factors have been reported to regulate GFAT1 expression and activity in cancers, such as mTOR complex, AMPK, and c-Myc [11,14,15]. However, the cellular oncogenic roles of GFAT1 and its underlying mechanism in PDAC are not clear.…”

Section: Introductionmentioning

confidence: 99%

GFAT1/HBP/O‐GlcNAcylation Axis Regulates β‐Catenin Activity to Promote Pancreatic Cancer Aggressiveness

Jia

et al. 2020

BioMed Research International

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Reprogrammed glucose and glutamine metabolism are essential for tumor initiation and development. As a branch of glucose and metabolism, the hexosamine biosynthesis pathway (HBP) generates uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) and contributes to the O-GlcNAcylation process. However, the spectrum of HBP-dependent tumors and the mechanisms by which the HBP promotes tumor aggressiveness remain areas of active investigation. In this study, we analyzed the activity of the HBP and its prognostic value across 33 types of human cancers. Increased HBP activity was observed in pancreatic ductal adenocarcinoma (PDAC), and higher HBP activity predicted a poor prognosis in PDAC patients. Genetic silencing or pharmacological inhibition of the first and rate-limiting enzyme of the HBP, glutamine:fructose-6-phosphate amidotransferase 1 (GFAT1), inhibited PDAC cell proliferation, invasive capacity, and triggered cell apoptosis. Notably, these effects can be restored by addition of UDP-GlcNAc. Moreover, similar antitumor effects were noticed by pharmacological inhibition of GFAT1 with 6-diazo-5-oxo-lnorleucine (DON) or Azaserine. PDAC is maintained by oncogenic Wnt/β-catenin transcriptional activity. Our data showed that GFAT1 can regulate β-catenin expression via modulation of the O-GlcNAcylation process. TOP/FOP-Flash and real-time qPCR analysis showed that GFAT1 knockdown inhibited β-catenin activity and the transcription of its downstream target genes CCND1 and MYC. Ectopic expression of a stabilized form of β-catenin restored the suppressive roles of GFAT1 knockdown on PDAC cell proliferation and invasion. Collectively, our findings indicate that higher GFAT1/HBP/O-GlcNAcylation exhibits tumor-promoting roles by maintaining β-catenin activity in PDAC.

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Mammalian Target of Rapamycin 2 (MTOR2) and C-MYC Modulate Glucosamine-6-Phosphate Synthesis in Glioblastoma (GBM) Cells Through Glutamine: Fructose-6-Phosphate Aminotransferase 1 (GFAT1)

Cited by 28 publications

References 51 publications

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

Combination of Rapamycin and MK-2206 Induced Cell Death via Autophagy and Necroptosis in MYCN-Amplified Neuroblastoma Cell Lines

Inhibition of Metabolic Shift can Decrease Therapy Resistance in Human High-Grade Glioma Cells

GFAT1/HBP/O‐GlcNAcylation Axis Regulates β‐Catenin Activity to Promote Pancreatic Cancer Aggressiveness

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