Tumor‐associated macrophage interleukin‐β promotes glycerol‐3‐phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells

Lu, Jianmin; Xu, Zhongye; Duan, Hubin; Ji, Hongming; Zhen, Zigang; Li, Bo; Wang, Huangsuo; Tang, Huoquan; Zhou, Jie; Guo, Tao; Wu, Bin; Wang, Dawei; Liu, Yueting; Zhang, Ruisheng

doi:10.1111/cas.14408

Cited by 50 publications

(46 citation statements)

References 47 publications

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“…Moreover, the median survival of glioblastoma is less than two years [3], which is in urgent need of novel treatment modalities. Tumor-associated M2 macrophages is reported to play a central role in tumor development [4]. Hypoxia and M2-like macrophages are correlated with poor prognosis of glioblastoma [5].…”

Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

Zhao

Ding

et al. 2020

Preprint

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Background: M2 macrophage polarization has been found to be correlated with malignancy of glioblastoma. In this study, we investigated the potential role of microRNA (miRNA) derived from extracellular vesicles of glioblastoma (glioblastoma-EVs) in M2 macrophage polarization.Methods: After isolation of human glioblastoma-EVs, transmission electron microscopy (TEM) and Nano-particle tracking analysis (NTA) were performed to identify the EVs. Besides, the proliferation, migration and invasion of glioma cells were analyzed by CCK8 and Transwell assays, respectively. The target genes of miR-27a-3p were predicted through bioinformatics analysis and verified by dual-luciferase reporter gene assay. ChIP assay was applied to detect the binding of enhancer of zeste homologue 1 (EZH1) to lysine-specific demethylase 3A (KDM3A) promoter region and the interaction between KDM3A and connective tissue growth factor (CTGF). Glioblastoma mouse models were established followed by the implement of hematoxylin-eosin (HE) and ELISA staining on pathological changes of mouse brain tissues.Results: Human glioblastoma-EVs were successfully isolated. The high expression of miR-27a-3p was found in glioblastoma tissues as well as glioblastoma-EVs, which could induce M2 polarization, thus promoting glioblastoma cell proliferation, migration and invasion. It was also shown that miR-27a-3p targeted EZH1 and promoted KDM3A expression to elevate the expression of CTGF. Glioblastoma-EVs delivered miR-27a-3p to promote the KDM3A-upregulated CTGF by downregulating EZH1, thereby promoting M2 macrophage polarization and development of glioblastoma in vivo.Conclusion: These findings highlight that EV miR-27a-3p may promote M2 macrophage polarization, which is associated with the progression of tumors.

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Section: Introductionmentioning

confidence: 99%

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

Zhao

Ding

et al. 2020

Preprint

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“…Furthermore, upregulated CAIX leads to TAM M2 polarization, indicating an immunosuppressive phenotype in glioma [ 71 ]. M2 TAMs produce IL-1β, which in turn leads to phosphorylation of the glycolytic enzyme GA3PDH in glioma cells through PIK3-mediated activation of protein kinase (PK)Cδ [ 171 ]. Blocking of the respective factors reduces the glycolytic rate and proliferation of glioma cells.…”

Section: Implications For Diagnostics and Therapymentioning

confidence: 99%

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Reuss

Groos

Buchfelder

et al. 2021

IJMS

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Malignant glioma represents a fatal disease with a poor prognosis and development of resistance mechanisms against conventional therapeutic approaches. The distinct tumor zones of this heterogeneous neoplasm develop their own microenvironment, in which subpopulations of cancer cells communicate. Adaptation to hypoxia in the center of the expanding tumor mass leads to the glycolytic and angiogenic switch, accompanied by upregulation of different glycolytic enzymes, transporters, and other metabolites. These processes render the tumor microenvironment more acidic, remodel the extracellular matrix, and create energy gradients for the metabolic communication between different cancer cells in distinct tumor zones. Escape mechanisms from hypoxia-induced cell death and energy deprivation are the result. The functional consequences are more aggressive and malignant behavior with enhanced proliferation and survival, migration and invasiveness, and the induction of angiogenesis. In this review, we go from the biochemical principles of aerobic and anaerobic glycolysis over the glycolytic switch, regulated by the key transcription factor hypoxia-inducible factor (HIF)-1α, to other important metabolic players like the monocarboxylate transporters (MCTs)1 and 4. We discuss the metabolic symbiosis model via lactate shuttling in the acidic tumor microenvironment and highlight the functional consequences of the glycolytic switch on glioma malignancy. Furthermore, we illustrate regulation by micro ribonucleic acids (miRNAs) and the connection between isocitrate dehydrogenase (IDH) mutation status and glycolytic metabolism. Finally, we give an outlook about the diagnostic and therapeutic implications of the glycolytic switch and the relation to tumor immunity in malignant glioma.

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“…In addition, activation of PKCδ in glioma cells activates glycerol-3-phosphate dehydrogenase (GPDH), an essential enzyme in several glioma cell functions due to its basic functions in glycolysis, respiration and phospholipid biosynthesis. Additionally, phosphorylation of GPDH at threonine 10 correlates with the levels of p-PKCδ in human GBM and with the local number of macrophages within the zone releasing IL-1β, which negatively affects tumor grade and patient survival [ 132 ], depicting a role for PKCδ in GBM growth and progression.…”

Section: Protein Kinase C and Glioblastomamentioning

confidence: 99%

Targeting Protein Kinase C in Glioblastoma Treatment

et al. 2021

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Glioblastoma (GBM) is the most frequent and aggressive primary brain tumor and is associated with a poor prognosis. Despite the use of combined treatment approaches, recurrence is almost inevitable and survival longer than 14 or 15 months after diagnosis is low. It is therefore necessary to identify new therapeutic targets to fight GBM progression and recurrence. Some publications have pointed out the role of glioma stem cells (GSCs) as the origin of GBM. These cells, with characteristics of neural stem cells (NSC) present in physiological neurogenic niches, have been proposed as being responsible for the high resistance of GBM to current treatments such as temozolomide (TMZ). The protein Kinase C (PKC) family members play an essential role in transducing signals related with cell cycle entrance, differentiation and apoptosis in NSC and participate in distinct signaling cascades that determine NSC and GSC dynamics. Thus, PKC could be a suitable druggable target to treat recurrent GBM. Clinical trials have tested the efficacy of PKCβ inhibitors, and preclinical studies have focused on other PKC isozymes. Here, we discuss the idea that other PKC isozymes may also be involved in GBM progression and that the development of a new generation of effective drugs should consider the balance between the activation of different PKC subtypes.

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Tumor‐associated macrophage interleukin‐β promotes glycerol‐3‐phosphate dehydrogenase activation, glycolysis and tumorigenesis in glioma cells

Cited by 50 publications

References 47 publications

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

WITHDRAWN: Glioblastoma cell-derived extracellular vesicle miR-27a-3p facilitates M2 macrophage polarization

The Acidic Brain—Glycolytic Switch in the Microenvironment of Malignant Glioma

Targeting Protein Kinase C in Glioblastoma Treatment

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