Endoplasmic reticulum regulation of glucose metabolism in glioma stem cells

Turos‑Cabal,María; Turos‑Cabal,María; Sánchez‑Sánchez,Ana M.; Sánchez‑Sánchez,Ana M.; Puente‑Moncada,Noelia; Puente‑Moncada,Noelia; Herrera,Federico; Herrera,Federico; Rodriguez‑Blanco,Jezabel; Rodriguez‑Blanco,Jezabel; Antolin,Isaac; Antolin,Isaac; Alvarez‑Vega,Marco Antonio; Alvarez‑Vega,Marco Antonio; Rodríguez,Carmen; Rodríguez,Carmen; Martín,Vanesa; Martín,Vanesa

doi:10.3892/ijo.2023.5589

Endoplasmic reticulum regulation of glucose metabolism in glioma stem cells

Authors:
- María Turos‑Cabal
- Ana M. Sánchez‑Sánchez
- Noelia Puente‑Moncada
- Federico Herrera
- Jezabel Rodriguez‑Blanco
- Isaac Antolin
- Marco Antonio Alvarez‑Vega
- Carmen Rodríguez
- Vanesa Martín
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Affiliations: Morphology and Cellular Biology Department, Faculty of Medicine, University of Oviedo, Oviedo 33006, Spain, Department of Chemistry and Biochemistry (DQB), Faculty of Sciences, University of Lisbon, Lisbon 1749‑016, Portugal, Darby Children's Research Institute, Department of Pediatrics, Medical University of South Carolina, Charleston, SC 29425, USA, Oncology Institute of Principality of Asturias (IUOPA), University of Oviedo, Oviedo 33006, Spain
Published online on: November 7, 2023 https://doi.org/10.3892/ijo.2023.5589
Article Number: 1

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Abstract

Glioblastoma (GBM) treatment is extremely challenging due to the high complexity of the tumor. It is one of the tumors in which a subpopulation of highly resistant glioma initiating cells (GICs) has been clearly identified. Thus, understanding the differences between GICs and tumor bulk cells is therefore essential to move to less conventional but more efficient approaches. It was found that, unlike their differentiated progeny, GICs survival and maintenance of stem cell properties depend on mitochondrial metabolism. GICs present higher glucose uptake and mitochondrial membrane potential and reduced lactate dehydrogenase activity, being more sensitive to mitochondrial inhibition than their differentiated counterparts. Calcium flux to the mitochondria appears to play an essential role in the maintenance of this distinct metabolic phenotype with a decrease in the expression of voltage‑dependent anionic channel (VDAC) and Grp75, two of the proteins of the IP3R‑Grp75‑VDAC complex that transfers calcium from the endoplasmic reticulum (ER) to the mitochondria. Disruption of ER homeostasis using ER stress inducers or inhibition of ER‑mitochondrial contact sites using the Grp75 inhibitor MKT‑077 resulted in cytotoxicity of GICs and loss of stemness. Moreover, MKT‑077 also potentiates the effect of temozolomide, current treatment for glioblastoma. In summary, the present data indicated that ER‑mitochondrial homeostasis is essential for regulation of GICs glucose metabolism and survival.

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1	Hussain SF, Yang D, Suki D, Aldape K, Grimm E and Heimberger AB: The role of human glioma-infiltrating Mi-croglia/Macrophages in mediating antitumor immune responses. Neuro Oncol. 8:261–279. 2006. View Article : Google Scholar : PubMed/NCBI
2	Charalambous C, Chen T and Hofman FM: Characteristics of tumor-associated endothelial cells derived from glioblastoma multiforme. Neurosurg Focus. 20:E222006. View Article : Google Scholar : PubMed/NCBI
3	Castro MG, Cowen R, Williamson IK, David A, Jimenez-Dalmaroni MJ, Yuan X, Bigliari A, Williams JC, Hu J and Lowenstein PR: Current and future strategies for the treatment of malignant brain tumors. Pharmacol Ther. 98:71–108. 2003. View Article : Google Scholar : PubMed/NCBI
4	Binello E and Germano IM: Targeting glioma stem cells: A novel framework for brain tumors. Cancer Sci. 102:1958–1966. 2011. View Article : Google Scholar : PubMed/NCBI
5	Suvà ML, Rheinbay E, Gillespie SM, Patel AP, Wakimoto H, Rabkin SD, Riggi N, Chi AS, Cahill DP, Nahed BV, et al: Reconstructing and reprogramming the tumor-propagating potential of glioblastoma stem-like cells. Cell. 157:580–594. 2014. View Article : Google Scholar : PubMed/NCBI
6	Bao S, Wu Q, McLendon RE, Hao Y, Shi Q, Hjelmeland AB, Dewhirst MW, Bigner DD and Rich JN: Glioma stem cells promote radioresistance by preferential activation of the DNA damage response. Nature. 444:756–760. 2006. View Article : Google Scholar : PubMed/NCBI
7	Menendez JA, Corominas-Faja B, Cuyàs E and Alarcón T: Metabostemness: Metaboloepigenetic reprogramming of cancer stem-cell functions. Oncoscience. 1:803–806. 2014. View Article : Google Scholar : PubMed/NCBI
8	Hanahan D and Weinberg RA: Hallmarks of cancer: The next generation. Cell. 144:646–674. 2011. View Article : Google Scholar : PubMed/NCBI
9	Vander Heiden MG, Cantley LC and Thompson CB: Understanding the Warburg Effect: The metabolic requirements of cell proliferation. Science. 324:1029–1033. 2009. View Article : Google Scholar : PubMed/NCBI
10	Brand KA and Hermfisse U: Aerobic glycolysis by proliferating cells: A protective strategy against reactive oxygen species. FASEB J. 11:388–395. 1997. View Article : Google Scholar : PubMed/NCBI
11	Menendez JA, Joven J, Cufí S, Corominas-Faja B, Oliveras-Ferraros C, Cuyàs E, Martin-Castillo B, Lopez-Bonet E, Alarcón T and Vazquez-Martin A: The warburg effect version 2.0: Metabolic reprogramming of cancer stem cells. Cell Cycle. 12:1166–1179. 2013. View Article : Google Scholar : PubMed/NCBI
12	Vlashi E, Lagadec C, Vergnes L, Matsutani T, Masui K, Poulou M, Popescu R, Della Donna L, Evers P, Dekmezian C, et al: Metabolic state of glioma stem cells and nontumorigenic cells. Proc Natl Acad Sci USA. 108:16062–16067. 2011. View Article : Google Scholar : PubMed/NCBI
13	Martin V, Turos-Cabal M, Sanchez-Sanchez AM and Rodríguez C: Metabolism-redox interplay in tumor stem cell signaling. Handbook of oxidative stress in cancer: Mechanistic Aspects. pp1–22. 2021. View Article : Google Scholar
14	Lin H, Patel S, Affeck VS, Wilson I, Turnbull DM, Joshi AR, Maxwell R and Stoll EA: Fatty acid oxidation is Required for the respiration and proliferation of malignant glioma cells. Neuro Oncol. 19:43–54. 2017. View Article : Google Scholar : PubMed/NCBI
15	Wang M and Kaufman RJ: The impact of the endoplasmic reticulum protein-folding environment on cancer development. Nat Rev Cancer. 14:581–597. 2014. View Article : Google Scholar : PubMed/NCBI
16	Rowland AA and Voeltz GK: Endoplasmic reticulum-mitochondria contacts: Function of the junction. Nat Rev Mol Cell Biol. 13:607–625. 2012. View Article : Google Scholar : PubMed/NCBI
17	Cardenas C, Miller RA, Smith I, Bui T, Molgo J, Müller M, Vais H, Cheung KH, Yang J, Parker I, et al: Essential regulation of cell bioenergetics by constitutive InsP3 Receptor Ca2+ Transfer to Mitochondria. Cell. 142:270–283. 2010. View Article : Google Scholar : PubMed/NCBI
18	Arismendi-Morillo G, Castellano-Ramírez A and Seyfried TN: Ultrastructural characterization of the mitochon-dria-associated membranes abnormalities in human astrocytomas: Functional and therapeutics implications. Ultrastruct Pathol. 41:234–244. 2017. View Article : Google Scholar : PubMed/NCBI
19	Galli R, Binda E, Orfanelli U, Cipelletti B, Gritti A, de Vitis S, Fiocco R, Foroni C, Dimeco F and Vescovi A: Isolation and Characterization of Tumorigenic, Stem-like Neural Precursors from Human Glioblastoma. Cancer Res. 64:7011–7021. 2004. View Article : Google Scholar : PubMed/NCBI
20	Singh SK, Hawkins C, Clarke ID, Squire JA, Bayani J, Hide T, Henkelman RM, Cusimano MD and Dirks PB: Identification of human brain tumour initiating cells. Nature. 432:396–401. 2004. View Article : Google Scholar : PubMed/NCBI
21	Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2(−Delta Delta C(T)) method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI
22	Zheng H, Ying H, Wiedemeyer R, Yan H, Quayle SN, Ivanova EV, Paik JH, Zhang H, Xiao Y, Perry SR, et al: PLAGL2 regulates Wnt signaling to impede differentiation in neural stem cells and gliomas. Cancer Cell. 17:497–509. 2010. View Article : Google Scholar : PubMed/NCBI
23	Hong X, Chedid K and Kalkanis SN: Glioblastoma cell line-derived spheres in serum containing medium versus serum-free medium: A comparison of cancer stem cell properties. Int J Oncol. 41:1693–1700. 2012. View Article : Google Scholar : PubMed/NCBI
24	Kim EJ, Jin X, Kim OR, Ham SW, Park SH and Kim H: Glioma stem cells and their non-stem differentiated glioma cells exhibit differences in mitochondrial structure and function. Oncol Rep. 39:411–416. 2018.PubMed/NCBI
25	Gangemi RM, Griffero F, Marubbi D, Perera M, Capra MC, Malatesta P, Ravetti GL, Zona GL, Daga A and Corte G: SOX2 silencing in glioblastoma tumor-initiating cells causes stop of proliferation and loss of tumorigenicity. Stem Cells. 27:40–48. 2009. View Article : Google Scholar : PubMed/NCBI
26	Lopez-Bertoni H, Johnson A, Rui Y, Lal B, Sall S, Malloy M, Coulter JB, Lugo-Fagundo M, Shudir S, Khela H, et al: Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications. Signal Transduct Target Ther. 7:372022. View Article : Google Scholar : PubMed/NCBI
27	Contreras L, Drago I, Zampese E and Pozzan T: Mitochondria: The calcium connection. Biochim Biophys Acta. 1797:607–618. 2010. View Article : Google Scholar : PubMed/NCBI
28	Kopp MC, Larburu N, Durairaj V. Adams CJ and Ali MMU: UPR Proteins IRE1 and PERK Switch BiP from Chaperone to ER Stress Sensor. Nat Struct Mol Biol. 26:1053–1062. 2019. View Article : Google Scholar : PubMed/NCBI
29	Anelli T, Bergamelli L, Margittai E, Rimessi A, Fagioli C, Malgaroli A, Pinton P, Ripamonti M, Rizzuto R and Sitia R: Ero1α Regulates Ca2+ fluxes at the endoplasmic reticulum-mitochondria interface (MAM). Antioxid Redox Signal. 16:1077–1087. 2012. View Article : Google Scholar : PubMed/NCBI
30	Jung JW, Park SB, Lee SJ, Seo MS, Trosko JE and Kang KS: Metformin represses self-renewal of the human breast carcinoma stem cells via inhibition of estrogen receptor-mediated OCT4 Expression. PLoS One. 6:e280682011. View Article : Google Scholar : PubMed/NCBI
31	Mayer MJ, Klotz LH and Venkateswaran V: Metformin and prostate cancer stem cells: A novel therapeutic target. Prostate Cancer Prostatic Dis. 18:303–309. 2015. View Article : Google Scholar : PubMed/NCBI
32	Snyder V, Reed-Newman TC, Arnold L, Thomas SM and Anant S: Cancer stem cell metabolism and potential therapeutic targets. Front Oncol. 8:2032018. View Article : Google Scholar : PubMed/NCBI
33	Cannino G, Ciscato F, Masgras I, Sánchez-Martín C and Rasola A: Metabolic plasticity of tumor cell mitochondria. Front Oncol. 8:3332018. View Article : Google Scholar : PubMed/NCBI
34	Filadi R and Pozzan T: Generation and functions of second messengers microdomains. Cell Calcium. 58:405–414. 2015. View Article : Google Scholar : PubMed/NCBI
35	Tarasov AI, Griffiths EJ and Rutter GA: Regulation of ATP production by mitochondrial Ca(2+). Cell Calcium. 52:28–35. 2012. View Article : Google Scholar : PubMed/NCBI
36	Debeb BG, Lacerda L, Larson R, Wolfe AR, Krishnamurthy S, Reuben JM, Ueno NT, Gilcrease M and Woodward WA: Histone deacetylase inhibitor-induced cancer stem cells exhibit high pentose phosphate pathway metabolism. Oncotarget. 7:28329–28339. 2016. View Article : Google Scholar : PubMed/NCBI
37	Wang N, Wang C, Zhao H, He Y, Lan B, Sun L and Gao Y: The MAMs structure and its role in cell death. Cells. 10:6572021. View Article : Google Scholar : PubMed/NCBI
38	Arif T, Krelin Y, Nakdimon I, Benharroch D, Paul A, Dadon-Klein D and Shoshan-Barmatz V: VDAC1 is a molecular target in glioblastoma, with its depletion leading to reprogrammed metabolism and reversed oncogenic properties. Neuro Oncol. 19:951–964. 2017. View Article : Google Scholar : PubMed/NCBI
39	Yun CO, Bhargava P, Na Y, Lee JS, Ryu J, Kaul SC and Wadhwa R: Relevance of mortalin to cancer cell stemness and cancer therapy. Sci Rep. 7:420162017. View Article : Google Scholar : PubMed/NCBI
40	Wei B, Cao J, Tian JH, Yu CY, Huang Q, Yu JJ, Ma R, Wang J, Xu F and Wang LB: Mortalin maintains breast cancer stem cells stemness via activation of Wnt/GSK3β/β-Catenin signaling pathway. Am J Cancer Res. 11:2696–2716. 2021.PubMed/NCBI
41	Xu M, Zhang Y, Cui M, Wang X and Lin Z: Mortalin contributes to colorectal cancer by promoting proliferation and epithelial-mesenchymal transition. IUBMB Life. 72:771–781. 2020. View Article : Google Scholar : PubMed/NCBI
42	Takano S, Wadhwa R, Yoshii Y, Nose T, Kaul SC and Mitsui Y: Elevated levels of mortalin expression in human brain tumors. Exp Cell Res. 237:38–45. 1997. View Article : Google Scholar : PubMed/NCBI