CBMS-10 Methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis and ribosomal RNA

Abstract Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells including FOXM1, SOX2, SOX4, PROM1 and OLIG2, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation. In addition, inhibition of cholesterol synthesis with statin resulted in a phenotype similar to that of methionine removal and a decrease in stem cell markers and snoRNA ACA43. Moreover, suppression of FOXM1 decreased stem cell markers such as SOX4 and PROM1. The gene expression profile for cholesterol production was obtained from the Ivy Glioblastoma Atlas Project (IVYGAP) database and compared between tumour cells with relatively low methionine levels in area of pseudopalisading arrangement around necrosis and tumour cells in the infiltrating region, showing that cells cells in the infiltrating region have a higher capacity to produce cholesterol. Taken together, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis: especially SREBF2-FOXM1 and ACA43 axis with modification of ribosomal RNA.

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TAMI-62. METHIONINE METABOLISM CLOSELY RELATED WITH SELF-RENEW, PLURIPOTENCY AND CELL DEATH IN GICS THROUGH MODIFICATION OF CHOLESTEROL BIOSYNTHESIS, RIBOSOMAL RNA AND AUTOPHAGY

Neuro-Oncology ◽

10.1093/neuonc/noab196.844 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi211-vi211

Author(s):

Kiyotaka Yokogami ◽

Hideo Takeshima

Keyword(s):

Stem Cells ◽

Cell Death ◽

Ribosomal Rna ◽

Cell Activation ◽

Cultured Cells ◽

Cholesterol Metabolism ◽

Cholesterol Biosynthesis ◽

Dna Demethylation ◽

Methionine Metabolism ◽

Starting Point

Abstract Glioma initiating cells (GICs) are the source of glioma cells that have the ability to self-renew and pluripotency, which are treatment-resistant, starting point for relapse and eventual death despite multimodality therapy. Since high accumulation is observed in 11cMet-PET at the time of recurrence, it is important to understand the mechanism of tumor cell activation caused by the reorganization of methionine metabolism. We cultured cells in methionine-deprived culture medium and performed a comprehensive analysis, and found that methionine depletion markedly decreased proliferation and increasing cell death of GICs. Decreased SAM, which is synthesized intracellularly catalyzed by methionine adenosyltransferase (MAT) using methionine, triggered the following: (i) global DNA demethylation, (ii) hyper-methylation of signaling pathways regulating pluripotentcy of stem cells, (iii) decreased expression of the core-genes and pluripotent marker of stem cells, (iv) decreased cholesterol synthesis and increased excretion mainly through decreased SREBF2 and FOXM1, (v) down-regulation of the large subunit of ribosomal protein configured 28S and ACA43, snoRNA guiding the pseudouridylation of 28S ribosomal RNA, which has crucial role for translation and (vi) possible connection between methionine metabolism and pluripotency, protein synthesis through cholesterol metabolism: SREBF2-FOXM1 and ACA43 axis, respectively. (vii) Disruption of autophagy by insufficient formation of macroautophagosomes. In conclusion, methionine metabolism closely related with self-renew, pluripotency and cell death in GICs through modification of cholesterol biosynthesis, ribosomal RNA and autophagy.

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Stress resistant human embryonic stem cells as a potential source for the identification of novel cancer stem cell markers

Cancer Letters ◽

10.1016/j.canlet.2009.08.018 ◽

2010 ◽

Vol 289 (2) ◽

pp. 208-216 ◽

Cited By ~ 4

Author(s):

Shaker A. Mousa ◽

Thangirala Sudha ◽

Evgeny Dyskin ◽

Usawadee Dier ◽

Christine Gallati ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Embryonic Stem Cells ◽

Cancer Stem Cell ◽

Human Embryonic Stem Cells ◽

Embryonic Stem ◽

Stem Cell Markers ◽

Cell Markers ◽

Cancer Stem Cell Markers ◽

Potential Source

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N-Glycosylation Profile of Undifferentiated and Adipogenically Differentiated Human Bone Marrow Mesenchymal Stem Cells: Towards a Next Generation of Stem Cell Markers

Stem Cells and Development ◽

10.1089/scd.2013.0108 ◽

2013 ◽

Vol 22 (23) ◽

pp. 3100-3113 ◽

Cited By ~ 23

Author(s):

Houda Hamouda ◽

Mujib Ullah ◽

Markus Berger ◽

Michael Sittinger ◽

Rudolf Tauber ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Human Bone ◽

Human Bone Marrow ◽

Stem Cell Markers ◽

Next Generation ◽

Cell Markers ◽

Marrow Mesenchymal Stem Cells

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Cancer Stem Cell Markers: Classification and Their Significance in Cancer Stem Cells

Bioengineering and Cancer Stem Cell Concept ◽

10.1007/978-3-319-25670-2_4 ◽

2015 ◽

pp. 57-70 ◽

Cited By ~ 1

Author(s):

Mirjana Pavlovic ◽

Bela Balint

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cancer Stem Cell ◽

Stem Cell Markers ◽

Cell Markers ◽

Cancer Stem Cell Markers

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Abstract 260: Apigenin nanoparticle suppresses sphere formation in CD133+/ALDH1highprostate cancer stem cells through downregulation of stem cell markers

10.1158/1538-7445.am2018-260 ◽

2018 ◽

Author(s):

Rajnee Kanwal ◽

Sanjeev Shukla ◽

Agata A. Exner ◽

Andreas G. Tzakos ◽

Sanjay Gupta

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Cancer Stem Cells ◽

Stem Cell Markers ◽

Cell Markers ◽

Sphere Formation

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P080 Therapeutical effect of urine-derived stem cells on DSS-induced chronic model of mice

Journal of Crohn s and Colitis ◽

10.1093/ecco-jcc/jjz203.209 ◽

2020 ◽

Vol 14 (Supplement_1) ◽

pp. S175-S175

Author(s):

X R Wu ◽

C Zhou ◽

H S Liu ◽

L Xuan-hui ◽

T Hu ◽

...

Keyword(s):

Stem Cells ◽

Stem Cell ◽

Low Cost ◽

Stem Cell Markers ◽

Male Adult ◽

Hematopoietic Stem ◽

Cell Markers ◽

Murine Colitis ◽

Chronic Model

Abstract Background The application of stem cell therapy in the treatment of inflammatory bowel diseases (IBD) is limited because of the invasive approaches of stem cells. Urine-derived stem cells (USCs) were recently shown to have regenerative properties, which can be harvested in a safe, low-cost and non-invasive way. Methods Human USC were isolated and expanded from the urine of healthy male adult volunteers (n = 3, age arrange 24–30 years old). USC were characterised by cell surface marker expression profile and multipotent differentiation. In vivo therapeutic value of USC was assessed using murine colitis chronic model induced by dextran sulphate sodium (DSS). Results USC were positive for mesenchymal stem cell markers but were negative for hematopoietic stem cell markers. These cells differentiated into osteo-, adipo- and chondro-genic cell lineages. Systemic administration of USC significantly ameliorated the clinical and histopathological severity of colitis and increased the survival rate in chronic murine colitis model. Conclusion This study demonstrated that implantation of USC reduces inflammation in IBD rodent model, indicating that USC therapy serves as a potential cell-based therapeutic candidate for IBD.

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Undifferentiated mouse mesenchymal stem cells spontaneously express neural and stem cell markers Oct-4 and Rex-1

Cytotherapy ◽

10.1080/14653240600735875 ◽

2006 ◽

Vol 8 (3) ◽

pp. 228-242 ◽

Cited By ~ 49

Author(s):

F.M.J. Lamoury ◽

J. Croitoru-Lamoury ◽

B.J. Brew

Keyword(s):

Stem Cells ◽

Mesenchymal Stem Cells ◽

Stem Cell ◽

Stem Cell Markers ◽

Cell Markers

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Mac-1 and F4/80 Surface Markers Are Present on Murine Hematopoietic Stem Cells.

Blood ◽

10.1182/blood.v108.11.1677.1677 ◽

2006 ◽

Vol 108 (11) ◽

pp. 1677-1677

Author(s):

Toska J. Zomorodian ◽

Debbie Greer ◽

Kyle Wood ◽

Bethany Foster ◽

Delia Demers ◽

...

Keyword(s):

Stem Cells ◽

Bone Marrow ◽

Stem Cell ◽

Hematopoietic Stem Cells ◽

Muscle Fibers ◽

Stem Cell Marker ◽

Stem Cell Markers ◽

Surface Markers ◽

Hematopoietic Stem ◽

Cell Markers

Abstract Transplanted bone marrow donor cells with tissue specific phenotypes have been found in the brain, liver, heart, skin, lung, kidney, and gut of transplanted humans and mice. Such observations have led to the controversial hypothesis that hematopoietic stem cells (HSC) might be intrinsically plastic, and through transdifferentiation or fusion lead to the repair of damaged tissues throughout the body. Alternately, it is suggested that fusion of macrophages to the recipient cells may explain this phenomenon. We have shown recently that purified HSC are the cells responsible for GFP positive donor-derived muscle fibers in the recipient mice post bone marrow transplantation. However, further studies sorting for macrophage markers Mac-1 and F4/80 also resulted in donor-derived muscle fibers in the host. To address this discrepancy, we investigated subpopulations of Mac-1 and F4/80 positive cells, in the presence or absence of stem cell markers (Sca-1 and C-kit). We demonstrate that only the subpopulations of Mac-1 and F4/80 positive cells harboring stem cell markers, Sca-1 or c-kit, were capable of contributing to the regenerating muscle post transplantation. Furthermore, these same subpopulations demonstrated single cell High Proliferative Potential (HPP) (6–26%) in a 7 factor cytokine cocktail, compared to the Mac-1 or F4/80 cells with no stem cell markers (0%). Additionally, they demonstrated long-term engraftment in all three lineages at 1-year (average chimerism of 55% versus 0% in stem cell marker negative groups). These subpopulations were also evaluated for morphology using Hematoxylin/Eosin (H/E), Wright-Giemsa, and Nonspecific Esterase staining. In the Mac-1 and F4/80 positive groups, those negative for stem cell markers resembled differentiated cells of the myeloid origin (macrophages, granulocytes), while those with positive stem cell markers demonstrated stem cell characteristics. We did not observe any engraftability, donor-derived muscle fibers, or HPP potential for CD14 or cfms positive cells coexpressing stem cell markers, indicating that these markers are more appropriate for identifying macrophages. In conclusion, our studies demonstrate that both Mac-1 and F4/80 surface markers are present on HSC and therefore caution must be taken in the interpretation of data using these macrophage markers. It is reasonable to believe that the use of Mac-1 and/or F4/80 surface markers in a lineage depletion process may result in the loss of a subpopulation of stem cells, and other markers such as CD14 or c-fms may be more appropriate for eliminating differentiated macrophages.

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The effect of BMI-1 inhibition on brain cancer stem cells.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e13543 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e13543-e13543

Author(s):

Monal Mehta ◽

Atif J. Khan ◽

Hatem E. Sabaawy ◽

Bruce George Haffty

Keyword(s):

Stem Cells ◽

Cell Death ◽

Stem Cell ◽

Cancer Stem Cells ◽

Cell Lines ◽

Brain Cancer ◽

Insertion Site ◽

Stem Cell Markers ◽

Primary Cells ◽

Self Renewal

e13543 Background: Glioblastoma (GBM) is the most frequent and deadly brain cancer. Despite tolerance doses of radiation, control of tumor growth within the brain remains a formidable failure. Since the identification of brain cancer stem cells (BCSCs), efforts are underway to target the pathways regulating these cells. The role of Bmi-1 (B-cell specific MMLV insertion site-1), a polycomb member of chromatin-remodeling complex, in BCSCs self-renewal was elucidated. Here we utilize shRNA targeting or pharmacological inhibition of Bmi-1 in GBM cell lines and primary cells as a radiosensitizer to examine the effects of combination therapy on cell death and BCSCs differentiation. Methods: Cells were pre-treated with a Bmi-1 inhibitor before being irradiated. Serial neurosphere assay, a measure of self-renewal potential, was employed to study the effects of radiation, Bmi-1 inhibition, or the combination on BCSCs. The efficacy of this combination on cell death was assessed with MTT and clonogenic assays. Next, the abilities of the inhibitor and radiation to induce differentiation in GBM cell lines and primary cells were quantified. Further, by utilizing a novel zebrafish orthotropic xenograft model, small molecules targeting Bmi-1 and other BCSC pathways can be identified, and used to predict response to combination therapies. Results: Targeting of Bmi-1 in combination with radiation, specifically as a radiosensitizer, induced significant cell death in GBM cells, and was five-fold more effective than radiation only. Importantly, the neurosphere forming ability of BCSCs was severely compromised when the cells were treated with the combination, indicating a potent effect on the stem cell constituency. These effects may be due to loss of BCSC self-renewal potential, increased differentiation, and/or apoptosis as cells treated with the combination exhibited decreased expression of neural stem cell markers and abnormal phenotypes compared to single treatment. Conclusions: Targeting of Bmi-1 may eliminate the subpopulation of radioresistant BCSCs. Bmi-1 inhibition when combined with radiotherapy might provide an effective therapy for GBM patients specifically through its effect on BCSCs by affecting their survival, proliferation, and stem cell features.

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