Abstract 4241: Glioma stem cells perform oxidative phosphorylation, while the rest of glioma cells perform aerobic glycolysis

Abstract BackgroundGlioma stem cells (GSCs) are glioma cells with stemness and are responsible for a variety of malignant behaviors of glioma. Evidence has shown that signals from tumor microenvironment (TME) enhance stemness of glioma cells, but the identity of the signaling molecules and underlying mechanisms have been incompletely elucidated.MethodsHuman samples and glioma cell lines were cultured in vitro to determine the effects of viral infection by sphere formation, qRT-PCR, Western blot, FACS and immunofluorescence; for in vivo analysis, mice subcutaneous tumor model was carried; while bioinformatics analysis and qRT-PCR were applied for further mechanistic studies.ResultsIn this study, we show that infection of patient-derived glioma cells with adenovirus (ADV) increases the formation of tumor spheres. ADV infection upregulated stem cell markers, and the resultant tumor spheres held the capacities of self-renewal and multi-lineage differentiation, and had stronger potential to form xenograft tumors in immune-compromised mice. ADV promoted GSC formation likely via TLR9, because TLR9 was upregulated after ADV infection, and knockdown of TLR9 reduced ADV-induced GSCs. Consistently, MYD88, as well as total STAT3 and phosphorylated (p-)STAT3, were also upregulated in ADV-induced GSCs. Knockdown of MYD88 or pharmaceutical inhibition of STAT3 attenuated stemness of ADV-induced GSCs. Moreover, we found that ADV infection upregulated lncRNA NEAT1, which is downstream to TLRs and play important roles in cancer stem cells via multiple mechanisms including strengthening STAT3 signaling. Indeed, knockdown of NEAT1 impaired stemness of ADV-induced GSCs. Lastly, we show that HMGB1, a damage associated molecular pattern (DAMP) that also triggers TLR signaling, upregulated stemness markers in glioma cells.ConclusionsIn summary, our data indicate that ADV, which has been developed as vectors for gene therapy and oncolytic virus, promotes the formation of GSCs via TLR9/NEAT1/STAT3 signaling.

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Verteporfin inhibits oxidative phosphorylation and induces cell death specifically in glioma stem cells

FEBS Journal ◽

10.1111/febs.15187 ◽

2020 ◽

Vol 287 (10) ◽

pp. 2023-2036 ◽

Cited By ~ 4

Author(s):

Kenta Kuramoto ◽

Masahiro Yamamoto ◽

Shuhei Suzuki ◽

Tomomi Sanomachi ◽

Keita Togashi ◽

...

Keyword(s):

Stem Cells ◽

Cell Death ◽

Oxidative Phosphorylation ◽

Glioma Stem Cells

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RNAase III-Type Enzyme Dicer Regulates Mitochondrial Fatty Acid Oxidative Metabolism in Cardiac Mesenchymal Stem Cells

International Journal of Molecular Sciences ◽

10.3390/ijms20225554 ◽

2019 ◽

Vol 20 (22) ◽

pp. 5554 ◽

Cited By ~ 3

Author(s):

Xuan Su ◽

Yue Jin ◽

Yan Shen ◽

Il-man Kim ◽

Neal L. Weintraub ◽

...

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Oxidative Phosphorylation ◽

Oxidative Metabolism ◽

Gene Deletion ◽

Aerobic Glycolysis ◽

Critical Role ◽

Mitochondrial Oxidative Phosphorylation ◽

Metabolic Switch ◽

Mitochondrial Fatty Acid

Cardiac mesenchymal stem cells (C-MSC) play a key role in maintaining normal cardiac function under physiological and pathological conditions. Glycolysis and mitochondrial oxidative phosphorylation predominately account for energy production in C-MSC. Dicer, a ribonuclease III endoribonuclease, plays a critical role in the control of microRNA maturation in C-MSC, but its role in regulating C-MSC energy metabolism is largely unknown. In this study, we found that Dicer knockout led to concurrent increase in both cell proliferation and apoptosis in C-MSC compared to Dicer floxed C-MSC. We analyzed mitochondrial oxidative phosphorylation by quantifying cellular oxygen consumption rate (OCR), and glycolysis by quantifying the extracellular acidification rate (ECAR), in C-MSC with/without Dicer gene deletion. Dicer gene deletion significantly reduced mitochondrial oxidative phosphorylation while increasing glycolysis in C-MSC. Additionally, Dicer gene deletion selectively reduced the expression of β-oxidation genes without affecting the expression of genes involved in the tricarboxylic acid (TCA) cycle or electron transport chain (ETC). Finally, Dicer gene deletion reduced the copy number of mitochondrially encoded 1,4-Dihydronicotinamide adenine dinucleotide (NADH): ubiquinone oxidoreductase core subunit 6 (MT-ND6), a mitochondrial-encoded gene, in C-MSC. In conclusion, Dicer gene deletion induced a metabolic shift from oxidative metabolism to aerobic glycolysis in C-MSC, suggesting that Dicer functions as a metabolic switch in C-MSC, which in turn may regulate proliferation and environmental adaptation.

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Glioma stem cells and their non-stem differentiated glioma cells exhibit differences in mitochondrial structure and function

Oncology Reports ◽

10.3892/or.2017.6075 ◽

2017 ◽

Cited By ~ 2

Author(s):

Eun-Jung Kim ◽

Xiong Jin ◽

Ock Kim ◽

Seok Ham ◽

Sung-Hye Park ◽

...

Keyword(s):

Stem Cells ◽

Glioma Cells ◽

Structure And Function ◽

Glioma Stem Cells ◽

Mitochondrial Structure ◽

And Function

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The Roles of miRNA in Glioblastoma Tumor Cell Communication: Diplomatic and Aggressive Negotiations

International Journal of Molecular Sciences ◽

10.3390/ijms21061950 ◽

2020 ◽

Vol 21 (6) ◽

pp. 1950 ◽

Cited By ~ 4

Author(s):

Andrei Buruiană ◽

Ștefan Ioan Florian ◽

Alexandru Ioan Florian ◽

Teodora-Larisa Timiș ◽

Carmen Mihaela Mihu ◽

...

Keyword(s):

Stem Cells ◽

Endothelial Cells ◽

Cell Communication ◽

Glioma Cells ◽

Glioma Stem Cells ◽

Patient Stratification ◽

Egfr Signaling ◽

Egfr Signaling Pathway ◽

Target Therapies ◽

Novel Target

Glioblastoma (GBM) consists of a heterogeneous collection of competing cellular clones which communicate with each other and with the tumor microenvironment (TME). MicroRNAs (miRNAs) present various exchange mechanisms: free miRNA, extracellular vesicles (EVs), or gap junctions (GJs). GBM cells transfer miR-4519 and miR-5096 to astrocytes through GJs. Oligodendrocytes located in the invasion front present high levels of miR-219-5p, miR-219-2-3p, and miR-338-3p, all related to their differentiation. There is a reciprocal exchange between GBM cells and endothelial cells (ECs) as miR-5096 promotes angiogenesis after being transferred into ECs, whereas miR-145-5p acts as a tumor suppressor. In glioma stem cells (GSCs), miR-1587 and miR-3620-5p increase the proliferation and miR-1587 inhibits the hormone receptor co-repressor-1 (NCOR1) after EVs transfers. GBM-derived EVs carry miR-21 and miR-451 that are up-taken by microglia and monocytes/macrophages, promoting their proliferation. Macrophages release EVs enriched in miR-21 that are transferred to glioma cells. This bidirectional miR-21 exchange increases STAT3 activity in GBM cells and macrophages, promoting invasion, proliferation, angiogenesis, and resistance to treatment. miR-1238 is upregulated in resistant GBM clones and their EVs, conferring resistance to adjacent cells via the CAV1/EGFR signaling pathway. Decrypting these mechanisms could lead to a better patient stratification and the development of novel target therapies.

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ETMM-06. ELEVATED MITOCHONDRIAL TOM20 EXPRESSION SUPPRESSES GLIOMA MALIGNANCY BY ENHANCING OXIDATIVE PHOSPHORYLATION

Neuro-Oncology Advances ◽

10.1093/noajnl/vdab024.062 ◽

2021 ◽

Vol 3 (Supplement_1) ◽

pp. i15-i15

Author(s):

Mao Li ◽

Shuxin Zhang ◽

Wanchun Yang ◽

Yuan Yang ◽

Dejiang Pang ◽

...

Keyword(s):

Oxidative Phosphorylation ◽

Aerobic Glycolysis ◽

Malignant Gliomas ◽

Glioma Cells ◽

Integrative Approach ◽

Mitochondrial Outer Membrane ◽

Metabolic Switch ◽

Therapeutic Implications

Abstract BACKGROUND Malignant glioma display a metabolic shift towards aerobic glycolysis with reprogramming of mitochondrial oxidative phosphorylation (OXPHOs). However, the underlying mechanism for this metabolic switch in glioma is not well elucidated. Mitochondrial translocases of the outer/inner membrane (TOMs/TIMs) import proteins into mitochondria, and could thereby regulate OXPHOs. The objective of this study is to investigate the expression of TOM/TIM members in glioma, as well as their functional and therapeutic implications. METHODS Transcriptome sequencing (RNA-seq), real-time PCR, Western blot, and immunohistochemistry were used to identify Tom20 as a significantly downregulated TOM/TIM protein in 20 paired glioma/Peritumoral tissues. To study the biological function of Tom20 in glioma, we interrogated metabolic alterations in Tom20 overexpressed glioma cells by GC-MS metabolomics, acetyl-CoA assay, and Seahorse assay. We compared the cell proliferation and viability profiles between Tom20 overexpressed and control cells in vitro and in vivo. To investigate the therapeutic implication of Tom20 expression, we tested OXPHOs inhibitor metformin in Tom20 overexpressed cells and xenograft mouse models. RESULTS We find that Tom20, a critical component of the mitochondrial outer membrane translocases, is downregulated in malignant gliomas. Using an integrative approach spanning bioinformatic analysis, metabolomics, and functional approaches, we reveal that Tom20 elevation activates mitochondrial OXPHOs in glioma cells and reduces tumor malignancy. We also find that Tom20 upregulation sensitizes glioma cells to metformin in vitro, and improves the therapeutic efficacy of metformin in glioma in vivo. CONCLUSION Our work defines Tom20 as a glioma suppressor and an indicator of metformin treatment in glioma.

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Signaling Pathways Involved in Nutrient Sensing Control in Cancer Stem Cells: An Overview

Frontiers in Endocrinology ◽

10.3389/fendo.2021.627745 ◽

2021 ◽

Vol 12 ◽

Author(s):

Martha Robles-Flores ◽

Angela P. Moreno-Londoño ◽

M. Cristina Castañeda-Patlán

Keyword(s):

Stem Cells ◽

Cancer Stem Cells ◽

Oxidative Phosphorylation ◽

Cancer Cells ◽

Signaling Pathways ◽

Molecular Mechanisms ◽

Aerobic Glycolysis ◽

Oxygen Deficiency ◽

Adenosine Monophosphate ◽

Nutrient Sensing

Cancer cells characteristically have a high proliferation rate. Because tumor growth depends on energy-consuming anabolic processes, including biosynthesis of protein, lipid, and nucleotides, many tumor-associated conditions, including intermittent oxygen deficiency due to insufficient vascularization, oxidative stress, and nutrient deprivation, results from fast growth. To cope with these environmental stressors, cancer cells, including cancer stem cells, must adapt their metabolism to maintain cellular homeostasis. It is well- known that cancer stem cells (CSC) reprogram their metabolism to adapt to live in hypoxic niches. They usually change from oxidative phosphorylation to increased aerobic glycolysis even in the presence of oxygen. However, as opposed to most differentiated cancer cells relying on glycolysis, CSCs can be highly glycolytic or oxidative phosphorylation-dependent, displaying high metabolic plasticity. Although the influence of the metabolic and nutrient-sensing pathways on the maintenance of stemness has been recognized, the molecular mechanisms that link these pathways to stemness are not well known. Here in this review, we describe the most relevant signaling pathways involved in nutrient sensing and cancer cell survival. Among them, Adenosine monophosphate (AMP)-activated protein kinase (AMPK) pathway, mTOR pathway, and Hexosamine Biosynthetic Pathway (HBP) are critical sensors of cellular energy and nutrient status in cancer cells and interact in complex and dynamic ways.

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