View More View Less
  • 1 National Institute of Mental Health and Neuro Sciences (NIMHANS), India
  • | 2 National Institute of Mental Health and Neuro Sciences (NIMHANS), India
  • | 3 National Institute of Mental Health and Neuro Sciences (NIMHANS), India
  • | 4 All India Institute of Medical Sciences (AIIMS), India
Restricted access

Purchase article

USD  $25.00

1 year subscription (Individual Only)

USD  $752.00

Purpose

Glioblastoma cells create glutamate-rich tumor microenvironment, which initiates activation of ion channels and modulates downstream intracellular signaling. N-methyl-D-aspartate receptors (NMDARs; a type of glutamate receptors) have a high affinity for glutamate. The role of NMDAR activation on invasion of glioblastoma cells and the crosstalk with α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors (AMPARs) is yet to be explored.

Main methods

LN18, U251MG, and patient-derived glioblastoma cells were stimulated with NMDA to activate NMDAR glutamate receptors. The role of NMDAR activation on invasion and migration and its crosstalk with AMPAR were evaluated. Invasion and migration of glioblastoma cells were investigated by in vitro trans-well Matrigel invasion and trans-well migration assays, respectively. Expression of NMDARs and AMPARs at transcript level was evaluated by quantitative real-time polymerase chain reaction.

Results

We determined that NMDA stimulation leads to enhanced invasion in LN18, U251MG, and patient-derived glioblastoma cells, whereas inhibition of NMDAR using MK-801, a non-competitive antagonist of the NMDAR, significantly decreased the invasive capacity. Concordant with these findings, migration was significantly augmented by NMDAR in both cell lines. Furthermore, NMDA stimulation upregulated the expression of GluN2 and GluA1 subunits at the transcript level.

Conclusions

This study demonstrated the previously unexplored role of NMDAR in invasion of glioblastoma cells. Furthermore, the expression of the GluN2 subunit of NMDAR and the differential overexpression of the GluA1 subunit of AMPAR in both cell lines provide a plausible rationale of crosstalk between these calcium-permeable subunits in the glutamate-rich microenvironment of glioblastoma.

  • 1.

    Altinoz MA , Elmaci I : Targeting nitric oxide and NMDA receptor-associated pathways in treatment of high grade glial tumors. Hypotheses for nitro-memantine and nitrones. Nitric Oxide 79, 6883 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 2.

    Bai N , Hayashi H , Aida T , Namekata K , Harada T , Mishina M , Tanaka K : Dock3 interaction with a glutamate-receptor NR2D subunit protects neurons from excitotoxicity. Mol. Brain. 6, 22 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 3.

    Belkaid A , Currie JC , Desgagnes J , Annabi B : The chemopreventive properties of chlorogenic acid reveal a potential new role for the microsomal glucose-6-phosphate translocase in brain tumor progression. Cancer Cell Int. 6, 7 (2006)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 4.

    Blough MD , Beauchamp DC , Westgate MR , Kelly JJ , Cairncross JG : Effect of aberrant p53 function on temozolomide sensitivity of glioma cell lines and brain tumor initiating cells from glioblastoma. J. Neurooncol. 102, 17 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 5.

    Cacciatore I , Fornasari E , Marinelli L , Eusepi P , Ciulla M , Ozdemir O , Tatar A , Turkez H , Di Stefano A : Memantine-derived drugs as potential antitumor agents for the treatment of glioblastoma. Eur. J. Pharm. Sci. 109, 402411 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 6.

    de Groot J , Sontheimer H : Glutamate and the biology of gliomas. Glia 59, 11811189 (2011)

  • 7.

    Fathima Hurmath K , Ramaswamy P , Nandakumar DN : IL-1beta microenvironment promotes proliferation, migration, and invasion of human glioma cells. Cell Biol. Int. 38, 14151422 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 8.

    Gielen M , Siegler Retchless B , Mony L , Johnson JW , Paoletti P : Mechanism of differential control of NMDA receptor activity by NR2 subunits. Nature 459, 703707 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 9.

    Hanahan D , Weinberg RA : Hallmarks of cancer: the next generation. Cell 144, 646674 (2011)

  • 10.

    Hoelzinger DB , Demuth T , Berens ME : Autocrine factors that sustain glioma invasion and paracrine biology in the brain microenvironment. J. Natl. Cancer Inst. 99, 15831593 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 11.

    Ishiuchi S , Tsuzuki K , Yoshida Y , Yamada N , Hagimura N , Okado H , Miwa A , Kurihara H , Nakazato Y , Tamura M , Sasaki T , Ozawa S : Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells. Nat. Med. 8, 971978 (2002)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 12.

    Ishiuchi S , Yoshida Y , Sugawara K , Aihara M , Ohtani T , Watanabe T , Saito N , Tsuzuki K , Okado H , Miwa A , Nakazato Y , Ozawa S : Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J. Neurosci. 27, 79878001 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 13.

    Justus CR , Leffler N , Ruiz-Echevarria M , Yang LV : In vitro cell migration and invasion assays. J. Vis. Exp. 88, e51046 (2014)

  • 14.

    Kim JY , Kim YJ , Lee S , Park JH : The critical role of ERK in death resistance and invasiveness of hypoxia-selected glioblastoma cells. BMC Cancer 9, 27 (2009)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 15.

    Kim MJ , Dunah AW , Wang YT , Sheng M : Differential roles of NR2A- and NR2B-containing NMDA receptors in Ras-ERK signaling and AMPA receptor trafficking. Neuron 46, 745760 (2005)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 16.

    Komuro H , Rakic P : Modulation of neuronal migration by NMDA receptors. Science 260, 9597 (1993)

  • 17.

    Lee JJ , Kim BC , Park MJ , Lee YS , Kim YN , Lee BL , Lee JS : PTEN status switches cell fate between premature senescence and apoptosis in glioma exposed to ionizing radiation. Cell Death Differ. 18, 666677 (2011)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 18.

    Lyons SA , Chung WJ , Weaver AK , Ogunrinu T , Sontheimer H : Autocrine glutamate signaling promotes glioma cell invasion. Cancer Res. 67, 94639471 (2007)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 19.

    Manini I , Caponnetto F , Bartolini A , Ius T , Mariuzzi L , Di Loreto C , Beltrami AP , Cesselli D : Role of microenvironment in glioma invasion: what we learned from in vitro models. Int. J. Mol. Sci. 19, 147 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 20.

    Oh MC , Kim JM , Safaee M , Kaur G , Sun MZ , Kaur R , Celli A , Mauro TM , Parsa AT : Overexpression of calcium-permeable glutamate receptors in glioblastoma derived brain tumor initiating cells. PLoS One 7, e47846 (2012)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 21.

    Poddar R , Chen A , Winter L , Rajagopal S , Paul S : Role of AMPA receptors in homocysteine-NMDA receptor-induced crosstalk between ERK and p38 MAPK. J. Neurochem. 142, 560573 (2017)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 22.

    Ramaswamy P , Aditi Devi N , Hurmath Fathima K , Dalavaikodihalli Nanjaiah N : Activation of NMDA receptor of glutamate influences MMP-2 activity and proliferation of glioma cells. Neurol. Sci. 35, 823829 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 23.

    Ramaswamy P , Goswami K , Nanjaiah ND , Srinivas D , Prasad C : TNF-alpha mediated MEK-ERK signaling in invasion with putative network involving NF-kappaB and STAT-6: a new perspective in glioma. Cell Biol. Int. 6 March 2019. doi:10.1002/cbin.11125 [Epub ahead of print]

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 24.

    Shipton OA , Paulsen O : GluN2A and GluN2B subunit-containing NMDA receptors in hippocampal plasticity. Philos. Trans. R. Soc. Lond. B Biol. Sci. 369, 20130163 (2014)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 25.

    Simeone TA , Sanchez RM , Rho JM : Molecular biology and ontogeny of glutamate receptors in the mammalian central nervous system. J Child Neurol. 19, 343360; discussion 361 (2004)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 26.

    Takenaga K , Kozlova EN : Role of intracellular S100A4 for migration of rat astrocytes. Glia 53, 313321 (2006)

  • 27.

    Van Brocklyn JR , Young N , Roof R : Sphingosine-1-phosphate stimulates motility and invasiveness of human glioblastoma multiforme cells. Cancer Lett. 199, 5360 (2003)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 28.

    Van Meir EG , Hadjipanayis CG , Norden AD , Shu HK , Wen PY , Olson JJ : Exciting new advances in neuro-oncology: the avenue to a cure for malignant glioma. CA Cancer J. Clin. 60, 166193 (2010)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 29.

    Viswanathan A , Zhurina A , Assoah B , Paakkunainen A , Musa A , Kute D , Saravanan KM , Yli-Harja O , Candeias NR , Kandhavelu M : Decane-1, 2-diol derivatives as potential antitumor agents for the treatment of glioblastoma. Eur. J. Pharmacol. 837, 105116 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 30.

    Wang HC , Lin YT , Lin WC , Ho RW , Lin YJ , Tsai NW , Ho JT , Lu CH : Tumor volume changes during and after temozolomide treatment for newly diagnosed higher-grade glioma (III and IV). World Neurosurg. 114, e766e774 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 31.

    Xu YB , Du QH , Zhang MY , Yun P , He CY : Propofol suppresses proliferation, invasion and angiogenesis by down-regulating ERK-VEGF/MMP-9 signaling in Eca-109 esophageal squamous cell carcinoma cells. Eur. Rev. Med. Pharmacol. Sci. 17, 24862494 (2013)

    • Search Google Scholar
    • Export Citation
  • 32.

    Yelskaya Z , Carrillo V , Dubisz E , Gulzar H , Morgan D , Mahajan SS : Synergistic inhibition of survival, proliferation, and migration of U87 cells with a combination of LY341495 and Iressa. PLoS One 8, e64588 (2013)

    • Crossref
    • Search Google Scholar
    • Export Citation
  • 33.

    Zhu Z , Du S , Du Y , Ren J , Ying G , Yan Z : Glutathione reductase mediates drug resistance in glioblastoma cells by regulating redox homeostasis. J. Neurochem. 144, 93104 (2018)

    • Crossref
    • Search Google Scholar
    • Export Citation
All Time Past Year Past 30 Days
Abstract Views 505 503 49
Full Text Views 120 73 0
PDF Downloads 63 38 0