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http://dx.doi.org/10.3340/jkns.2016.0101.006

Memantine Induces NMDAR1-Mediated Autophagic Cell Death in Malignant Glioma Cells  

Yoon, Wan-Soo (Department of Neurosurgery, Incheon St. Mary's Hospital, The Catholic University of Korea)
Yeom, Mi-Young (Clinical Research Laboratory, Incheon St. Mary's Hospital, The Catholic University of Korea)
Kang, Eun-Sun (Clinical Research Laboratory, Incheon St. Mary's Hospital, The Catholic University of Korea)
Chung, Yong-An (Institute of Catholic Integrative Medicine, Incheon St. Mary's Hospital, The Catholic University of Korea)
Chung, Dong-Sup (Department of Neurosurgery, Incheon St. Mary's Hospital, The Catholic University of Korea)
Jeun, Sin-Soo (Department of Neurosurgery, Seoul St. Mary's Hospital, The Catholic University of Korea)
Publication Information
Journal of Korean Neurosurgical Society / v.60, no.2, 2017 , pp. 130-137 More about this Journal
Abstract
Objective : Autophagy is one of the key responses of cells to programmed cell death. Memantine, an approved anti-dementia drug, has an antiproliferative effect on cancer cells but the mechanism is poorly understood. The aim of the present study was to test the possibility of induction of autophagic cell death by memantine in glioma cell lines. Methods : Glioma cell lines (T-98 G and U-251 MG) were used for this study. Results : The antiproliferative effect of memantine was shown on T-98 G cells, which expressed N-methyl-D-aspartate 1 receptor (NMDAR1). Memantine increased the autophagic-related proteins as the conversion ratio of light chain protein 3-II (LC3-II)-/LC3-I and the expression of beclin-1. Memantine also increased formation of autophagic vacuoles observed under a transmission electron microscope. Transfection of small interfering RNA (siRNA) to knock down NMDAR1 in the glioma cells induced resistance to memantine and decreased the LC3-II/LC3-I ratio in T-98 G cells. Conclusion : Our study demonstrates that in glioma cells, memantine inhibits proliferation and induces autophagy mediated by NMDAR1.
Keywords
Memantine; Autophagy; N-methyl-D-aspartate; Glioma;
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1 Stepulak A, Sifringer M, Rzeski W, Endesfelder S, Gratopp A, Pohl EE, et al. : NMDA antagonist inhibits the extracellular signal-regulated kinase pathway and suppresses cancer growth. Proc Natl Acad Sci USA 102 : 15605-15610, 2005   DOI
2 Chen M, Lu TJ, Chen XJ, Zhou Y, Chen Q, Feng XY, et al. : Differential roles of NMDA receptor subtypes in ischemic neuronal cell death and ischemic tolerance. Stroke 39 : 3042-3048, 2008   DOI
3 de Groot J, Sontheimer H : Glutamate and the biology of gliomas. Glia 59 : 1181-1189, 2011   DOI
4 de Groot JF, Piao Y, Lu L, Fuller GN, Yung WK : Knockdown of GluR1 expression by RNA interference inhibits glioma proliferation. J Neurooncol 88 : 121-133, 2008   DOI
5 Fan G, Sun B, Wu Z, Guo Q, Guo Y : In vivo single-voxel proton MR spectroscopy in the differentiation of high-grade gliomas and solitary metastases. Clin Radiol 59 : 77-85, 2004   DOI
6 Ishiuchi S, Yoshida Y, Sugawara K, Aihara M, Ohtani T, Watanabe T, et al. : Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci 27 : 7987-8001, 2007   DOI
7 Johnson JW, Kotermanski SE : Mechanism of action of memantine. Curr Opin Pharmacol 6 : 61-67, 2006   DOI
8 Kihara K, Kabeya Y, Ohsumi Y, Yoshimori T : Beclin-phosphatidylinositol 3-kinase complex functions at the trans-Golgi network. EMBO Rep 2 : 330-335, 2001   DOI
9 Klionsky DJ, Abdalla FC, Abeliovich H, Abraham RT, Acevedo-Arozena A, Adeli K, et al. : Guidelines for the use and interpretation of assays for monitoring autophagy. Autophagy 8 : 445-544, 2012   DOI
10 Liu Y, Wong TP, Aarts M, Rooyakkers A, Liu L, Lai TW, et al. : NMDA receptor subunits have differential roles in mediating excitotoxic neuronal death both in vitro and in vivo. J Neurosci 27 : 2846-2857, 2007   DOI
11 McComb RD, Burger PC : Pathologic analysis of primary brain tumors. Neurol Clin 3 : 711-728, 1985   DOI
12 Abdul M, Hoosein N : N-methyl-D-aspartate receptor in human prostate cancer. J Membr Biol 205 : 125-128, 2005   DOI
13 Adamson C, Kanu OO, Mehta AI, Di C, Lin N, Mattox AK, et al. : Glioblastoma multiforme: a review of where we have been and where we are going. Expert Opin Investig Drugs 18 : 1061-1083, 2009   DOI
14 Behrens PF, Langemann H, Strohschein R, Draeger J, Hennig J : Extracellular glutamate and other metabolites in and around RG2 rat glioma: an intracerebral microdialysis study. J Neurooncol 47 : 11-22, 2000   DOI
15 Besshoh S, Bawa D, Teves L, Wallace MC, Gurd JW : Increased phosphorylation and redistribution of NMDA receptors between synaptic lipid rafts and postsynaptic densities following transient global ischemia in the rat brain. J Neurochem 93 : 186-194, 2005   DOI
16 Bigford GE, Alonso OF, Dietrich D, Keane RW : A novel protein complex in membrane rafts linking the NR2B glutamate receptor and autophagy is disrupted following traumatic brain injury. J Neurotrauma 26 : 703-720, 2009   DOI
17 Witt A, Macdonald N, Kirkpatrick P : Memantine hydrochloride. Nat Rev Drug Discov 3 : 109-110, 2004   DOI
18 Surawicz TS, Davis F, Freels S, Laws ER Jr, Menck HR : Brain tumor survival: results from the National Cancer Data Base. J Neurooncol 40 : 151-160, 1998   DOI
19 Takano T, Lin JH, Arcuino G, Gao Q, Yang J, Nedergaard M : Glutamate release promotes growth of malignant gliomas. Nat Med 7 : 1010-1015, 2001   DOI
20 Watanabe K, Kanno T, Oshima T, Miwa H, Tashiro C, Nishizaki T : The NMDA receptor NR2A subunit regulates proliferation of MKN45 human gastric cancer cells. Biochem Biophys Res Commun 367 : 487-490, 2008   DOI
21 Ye ZC, Sontheimer H : Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59 : 4383-4391, 1999
22 Rijpkema M, Schuuring J, van der MY, van der GM, Bernsen H, Boerman R, et al. : Characterization of oligodendrogliomas using short echo time 1H MR spectroscopic imaging. NMR Biomed 16 : 12-18, 2003   DOI
23 Moots PL, Maciunas RJ, Eisert DR, Parker RA, Laporte K, Abou-Khalil B : The course of seizure disorders in patients with malignant gliomas. Arch Neurol 52 : 717-724, 1995   DOI
24 North WG, Gao G, Jensen A, Memoli VA, Du J : NMDA receptors are expressed by small-cell lung cancer and are potential targets for effective treatment. Clin Pharmacol 2 : 31-40, 2010
25 Piao Y, Lu L, de Groot J : AMPA receptors promote perivascular glioma invasion via beta1 integrin dependent adhesion to the extracellular matrix. Neuro Oncol 11 : 260-273, 2009   DOI
26 Rothman SM, Olney JW : Excitotoxicity and the NMDA receptor-still lethal after eight years. Trends Neurosci 18 : 57-58, 1995
27 Ruban A, Berkutzki T, Cooper I, Mohar B, Teichberg VI : Blood glutamate scavengers prolong the survival of rats and mice with brain-implanted gliomas. Invest New Drugs 30 : 2226-2235, 2012   DOI
28 Rzeski W, Turski L, Ikonomidou C : Glutamate antagonists limit tumor growth. Proc Natl Acad Sci USA 98 : 6372-6377, 2001   DOI
29 Schunemann DP, Grivicich I, Regner A, Leal LF, de Araujo DR, Jotz GP, et al. : Glutamate promotes cell growth by EGFR signaling on U-87MG human glioblastoma cell line. Pathol Oncol Res 16 : 285-293, 2010   DOI
30 Sontheimer H : A role for glutamate in growth and invasion of primary brain tumors. J Neurochem 105 : 287-295, 2008   DOI