Skip to main content

Advertisement

Springer Nature Link
Log in

The role of ion channels in malignant brain tumors

  • Topic Review
  • Published:
Journal of Neuro-Oncology Aims and scope Submit manuscript

Abstract

Malignant gliomas are the most common primary brain tumors and have poor clinical prognosis, despite multimodal therapeutic strategies. In recent years, ion channels have emerged as major players in tumor pathophysiology regarding all hallmarks of cancer. Since ion channels are easily accessible structures, they may prove to be effective targets for canner therapy, although their broad expression pattern and role in physiological processes should be taken into consideration. This review summarizes the current knowledge on the role of ion channels in the pathophysiology of malignant gliomas, especially glioblastoma, and evaluates their potential role in targeted antiglioma therapy.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Subscribe and save

Springer+ Basic
$34.99 /Month
  • Get 10 units per month
  • Download Article/Chapter or eBook
  • 1 Unit = 1 Article or 1 Chapter
  • Cancel anytime
Subscribe now

Buy Now

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

Explore related subjects

Discover the latest articles and news from researchers in related subjects, suggested using machine learning.

Abbreviations

AMPA:

α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

AQP:

Aquaporin

BK:

Big conductance potassium channel

ClC:

Chloride channel

CNS:

Central nervous system

EAG1:

Ether à go-go 1

GABAA :

γ-aminobutyric acid receptor A

gAMPA:

Glioma variant of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor

gBK:

Glioma variant of big conductance potassium channel

hERG1:

Human ether à go-go related 1

K2P:

Two-pore domain potassium channel

KA :

Inactivating A-type potassium channel

KCa3.1:

Calcium-dependent intermediate-conductance potassium channel 3.1

KCC3:

K+/Cl− cotransporter 3

KCNH2:

Potassium voltage-gated channel, subfamily H, member 2

KDR :

Delayed outwardly rectifying potassium channel

Kir :

Inwardly rectifying potassium channel

NBC:

Sodium/bicarbonate cotransporter

NHE:

Sodium/proton exchanger

NHERF1:

Sodium/proton exchanger regulatory factor 1

NKCC:

Na+/K/+/Cl− cotransporters

NKCC1:

Na+/K+/2Cl− cotransporter isoform 1

siRNA:

Small interfering ribonucleic acid

TEA:

Tetraethylammonium

TMZ:

Temozolomide

TRPC:

Transient receptor potential cation channel

TRPM8:

Transient receptor potential, melastatin subfamily member 8

VEGF:

Vascular endothelial growth factor

WHO:

World Health Organization

References

  1. Becchetti A (2011) Ion channels and transporters in cancer. 1. Ion channels and cell proliferation in cancer. Am J Physiol Cell Physiol 301:C255–C265

    Article  CAS  PubMed  Google Scholar 

  2. Soroceanu L, Manning TJ Jr, Sontheimer H (1999) Modulation of glioma cell migration and invasion using Cl(−) and K(+) ion channel blockers. J Neurosci 19:5942–5954

    CAS  PubMed  Google Scholar 

  3. Prevarskaya N, Skryma R, Shuba Y (2010) Ion channels and the hallmarks of cancer. Trends Mol Med 16:107–121

    Article  CAS  PubMed  Google Scholar 

  4. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A, Scheithauer BW, Kleihues P (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114:97–109

    Article  PubMed Central  PubMed  Google Scholar 

  5. Stupp R, Hegi ME, Mason WP, van den Bent MJ, Taphoorn MJ, Janzer RC, Ludwin SK, Allgeier A, Fisher B, Belanger K, Hau P, Brandes AA, Gijtenbeek J, Marosi C, Vecht CJ, Mokhtari K, Wesseling P, Villa S, Eisenhauer E, Gorlia T, Weller M, Lacombe D, Cairncross JG, Mirimanoff RO (2009) Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol 10:459–466

    Article  CAS  PubMed  Google Scholar 

  6. von Deimling A, Louis DN, Wiestler OD (1995) Molecular pathways in the formation of gliomas. Glia 15:328–338

    Article  Google Scholar 

  7. Louis DN (1994) The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 53:11–21

    Article  CAS  PubMed  Google Scholar 

  8. Ye ZC, Rothstein JD, Sontheimer H (1999) Compromised glutamate transport in human glioma cells: reduction-mislocalization of sodium-dependent glutamate transporters and enhanced activity of cystine-glutamate exchange. J Neurosci 19:10767–10777

    CAS  PubMed  Google Scholar 

  9. Ye ZC, Sontheimer H (1999) Glioma cells release excitotoxic concentrations of glutamate. Cancer Res 59:4383–4391

    CAS  PubMed  Google Scholar 

  10. Nakada M, Okada Y, Yamashita J (2003) The role of matrix metalloproteinases in glioma invasion. Front Biosci 8:e261–e269

    Article  CAS  PubMed  Google Scholar 

  11. Bordey A, Sontheimer H (2000) Ion channel expression by astrocytes in situ: comparison of different CNS regions. Glia 30:27–38

    Article  CAS  PubMed  Google Scholar 

  12. Hajek I, Subbarao KV, Hertz L (1996) Acute and chronic effects of potassium and noradrenaline on Na+, K+-ATPase activity in cultured mouse neurons and astrocytes. Neurochem Int 28:335–342

    Article  CAS  PubMed  Google Scholar 

  13. Charles AC, Merrill JE, Dirksen ER, Sanderson MJ (1991) Intercellular signaling in glial cells: calcium waves and oscillations in response to mechanical stimulation and glutamate. Neuron 6:983–992

    Article  CAS  PubMed  Google Scholar 

  14. Shigetomi E, Bowser DN, Sofroniew MV, Khakh BS (2008) Two forms of astrocyte calcium excitability have distinct effects on NMDA receptor-mediated slow inward currents in pyramidal neurons. J Neurosci 28:6659–6663

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  15. Nedergaard M, Ransom B, Goldman SA (2003) New roles for astrocytes: redefining the functional architecture of the brain. Trends Neurosci 26:523–530

    Article  CAS  PubMed  Google Scholar 

  16. Simard M, Nedergaard M (2004) The neurobiology of glia in the context of water and ion homeostasis. Neuroscience 129:877–896

    Article  CAS  PubMed  Google Scholar 

  17. Pasantes-Morales H, Cardin V, Tuz K (2000) Signaling events during swelling and regulatory volume decrease. Neurochem Res 25:1301–1314

    Article  CAS  PubMed  Google Scholar 

  18. Halassa MM, Fellin T, Haydon PG (2009) Tripartite synapses: roles for astrocytic purines in the control of synaptic physiology and behavior. Neuropharmacology 57:343–346

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Smits A, Jin Z, Elsir T, Pedder H, Nister M, Alafuzoff I, Dimberg A, Edqvist PH, Ponten F, Aronica E, Birnir B (2012) GABA-A channel subunit expression in human glioma correlates with tumor histology and clinical outcome. PLoS One 7:e37041

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. Garzon-Muvdi T, Schiapparelli P, ap Rhys C, Guerrero-Cazares H, Smith C, Kim DH, Kone L, Farber H, Lee DY, An SS, Levchenko A, Quinones-Hinojosa A (2012) Regulation of brain tumor dispersal by NKCC1 through a novel role in focal adhesion regulation. PLoS Biol 10:e1001320

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Arvind S, Arivazhagan A, Santosh V, Chandramouli BA (2012) Differential expression of a novel voltage gated potassium channel–Kv 1.5 in astrocytomas and its impact on prognosis in glioblastoma. Br J Neurosurg 26:16–20

    Article  CAS  PubMed  Google Scholar 

  22. Bielanska J, Hernandez-Losa J, Perez-Verdaguer M, Moline T, Somoza R, Ramon YCS, Condom E, Ferreres JC, Felipe A (2009) Voltage-dependent potassium channels Kv1.3 and Kv1.5 in human cancer. Curr Cancer Drug Targets 9:904–914

    Article  CAS  PubMed  Google Scholar 

  23. Basrai D, Kraft R, Bollensdorff C, Liebmann L, Benndorf K, Patt S (2002) BK channel blockers inhibit potassium-induced proliferation of human astrocytoma cells. NeuroReport 13:403–407

    Article  CAS  PubMed  Google Scholar 

  24. Chin LS, Park CC, Zitnay KM, Sinha M, DiPatri AJ Jr, Perillan P, Simard JM (1997) 4-Aminopyridine causes apoptosis and blocks an outward rectifier K+ channel in malignant astrocytoma cell lines. J Neurosci Res 48:122–127

    Article  CAS  PubMed  Google Scholar 

  25. Bordey A, Sontheimer H (1998) Electrophysiological properties of human astrocytic tumor cells In situ: enigma of spiking glial cells. J Neurophysiol 79:2782–2793

    CAS  PubMed  Google Scholar 

  26. Kraft R, Basrai D, Benndorf K, Patt S (2001) Serum deprivation and NGF induce and modulate voltage-gated Na(+) currents in human astrocytoma cell lines. Glia 34:59–67

    Article  CAS  PubMed  Google Scholar 

  27. Bubien JK, Keeton DA, Fuller CM, Gillespie GY, Reddy AT, Mapstone TB, Benos DJ (1999) Malignant human gliomas express an amiloride-sensitive Na+ conductance. Am J Physiol 276:C1405–C1410

    CAS  PubMed  Google Scholar 

  28. Schrey M, Codina C, Kraft R, Beetz C, Kalff R, Wolfl S, Patt S (2002) Molecular characterization of voltage-gated sodium channels in human gliomas. NeuroReport 13:2493–2498

    Article  CAS  PubMed  Google Scholar 

  29. Xing D, Wang J, Ou S, Wang Y, Qiu B, Ding D, Guo F, Gao Q (2014) Expression of neonatal Nav1.5 in human brain astrocytoma and its effect on proliferation, invasion and apoptosis of astrocytoma cells. Oncol Rep 31:2692–2700

    CAS  PubMed  Google Scholar 

  30. Yang M, Kozminski DJ, Wold LA, Modak R, Calhoun JD, Isom LL, Brackenbury WJ (2012) Therapeutic potential for phenytoin: targeting Na(v)1.5 sodium channels to reduce migration and invasion in metastatic breast cancer. Breast Cancer Res Treat 134(2):603–615

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Olsen ML, Schade S, Lyons SA, Amaral MD, Sontheimer H (2003) Expression of voltage-gated chloride channels in human glioma cells. J Neurosci 23:5572–5582

    CAS  PubMed  Google Scholar 

  32. Lui VC, Lung SS, Pu JK, Hung KN, Leung GK (2010) Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3. Anticancer Res 30:4515–4524

    CAS  PubMed  Google Scholar 

  33. Su J, Xu Y, Zhou L, Yu HM, Kang JS, Liu N, Quan CS, Sun LK (2013) Suppression of chloride channel 3 expression facilitates sensitivity of human glioma U251 cells to cisplatin through concomitant inhibition of Akt and autophagy. Anat Rec 296:595–603

    Article  CAS  Google Scholar 

  34. Algharabil J, Kintner DB, Wang Q, Begum G, Clark PA, Yang SS, Lin SH, Kahle KT, Kuo JS, Sun D (2012) Inhibition of Na(+)-K(+)-2Cl(−) cotransporter isoform 1 accelerates temozolomide-mediated apoptosis in glioblastoma cancer cells. Cell Physiol Biochem 30:33–48

    Article  CAS  PubMed  Google Scholar 

  35. Gagnon KB (2012) High-grade glioma motility reduced by genetic knockdown of KCC3. Cell Physiol Biochem 30:466–476

    Article  CAS  PubMed  Google Scholar 

  36. Olsen ML, Sontheimer H (2004) Mislocalization of Kir channels in malignant glia. Glia 46:63–73

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. MacFarlane SN, Sontheimer H (2000) Changes in ion channel expression accompany cell cycle progression of spinal cord astrocytes. Glia 30:39–48

    Article  CAS  PubMed  Google Scholar 

  38. Tan G, Sun SQ, Yuan DL (2008) Expression of Kir 4.1 in human astrocytic tumors: correlation with pathologic grade. Biochem Biophys Res Commun 367:743–747

    Article  CAS  PubMed  Google Scholar 

  39. Ransom CB, Sontheimer H (2001) BK channels in human glioma cells. J Neurophysiol 85:790–803

    CAS  PubMed  Google Scholar 

  40. Tseng-Crank J, Foster CD, Krause JD, Mertz R, Godinot N, DiChiara TJ, Reinhart PH (1994) Cloning, expression, and distribution of functionally distinct Ca(2+)-activated K+ channel isoforms from human brain. Neuron 13:1315–1330

    Article  CAS  PubMed  Google Scholar 

  41. Ransom CB, Liu X, Sontheimer H (2002) BK channels in human glioma cells have enhanced calcium sensitivity. Glia 38:281–291

    Article  PubMed  Google Scholar 

  42. Liu X, Chang Y, Reinhart PH, Sontheimer H (2002) Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells. J Neurosci 22:1840–1849

    CAS  PubMed  Google Scholar 

  43. Weaver AK, Liu X, Sontheimer H (2004) Role for calcium-activated potassium channels (BK) in growth control of human malignant glioma cells. J Neurosci Res 78:224–234

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  44. Wondergem R, Bartley JW (2009) Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration. J Biomed Sci 16:90

    Article  PubMed Central  PubMed  Google Scholar 

  45. Patt S, Preussat K, Beetz C, Kraft R, Schrey M, Kalff R, Schonherr K, Heinemann SH (2004) Expression of ether a go-go potassium channels in human gliomas. Neurosci Lett 368:249–253

    Article  CAS  PubMed  Google Scholar 

  46. Masi A, Becchetti A, Restano-Cassulini R, Polvani S, Hofmann G, Buccoliero AM, Paglierani M, Pollo B, Taddei GL, Gallina P, Di Lorenzo N, Franceschetti S, Wanke E, Arcangeli A (2005) hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines. Br J Cancer 93:781–792

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. D’Alessandro G, Catalano M, Sciaccaluga M, Chece G, Cipriani R, Rosito M, Grimaldi A, Lauro C, Cantore G, Santoro A, Fioretti B, Franciolini F, Wulff H, Limatola C (2013) KCa3.1 channels are involved in the infiltrative behavior of glioblastoma in vivo. Cell Death Dis 4:e773

    Article  PubMed Central  PubMed  Google Scholar 

  48. Turner KL, Honasoge A, Robert SM, McFerrin MM, Sontheimer H (2014) A proinvasive role for the Ca(2+) -activated K(+) channel KCa3.1 in malignant glioma. Glia 62:971–981

    Article  PubMed Central  PubMed  Google Scholar 

  49. Bittner S, Budde T, Wiendl H, Meuth SG (2010) From the background to the spotlight: TASK channels in pathological conditions. Brain Pathol 20:999–1009

    Article  CAS  PubMed  Google Scholar 

  50. Patel AJ, Lazdunski M (2004) The 2P-domain K+ channels: role in apoptosis and tumorigenesis. Pflugers Arch 448:261–273

    Article  CAS  PubMed  Google Scholar 

  51. Meuth SG, Herrmann AM, Ip CW, Kanyshkova T, Bittner S, Weishaupt A, Budde T, Wiendl H (2008) The two-pore domain potassium channel TASK3 functionally impacts glioma cell death. J Neurooncol 87:263–270

    Article  CAS  PubMed  Google Scholar 

  52. Ishiuchi S, Yoshida Y, Sugawara K, Aihara M, Ohtani T, Watanabe T, Saito N, Tsuzuki K, Okado H, Miwa A, Nakazato Y, Ozawa S (2007) Ca2+-permeable AMPA receptors regulate growth of human glioblastoma via Akt activation. J Neurosci 27:7987–8001

    Article  CAS  PubMed  Google Scholar 

  53. Zhang Y, Zhang J, Jiang D, Zhang D, Qian Z, Liu C, Tao J (2012) Inhibition of T-type Ca(2)(+) channels by endostatin attenuates human glioblastoma cell proliferation and migration. Br J Pharmacol 166:1247–1260

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Ding X, He Z, Zhou K, Cheng J, Yao H, Lu D, Cai R, Jin Y, Dong B, Xu Y, Wang Y (2010) Essential role of TRPC6 channels in G2/M phase transition and development of human glioma. J Natl Cancer Inst 102:1052–1068

    Article  CAS  PubMed  Google Scholar 

  55. Ross SB, Fuller CM, Bubien JK, Benos DJ (2007) Amiloride-sensitive Na+ channels contribute to regulatory volume increases in human glioma cells. Am J Physiol Cell Physiol 293(3):C1181–C1185

    Article  CAS  PubMed  Google Scholar 

  56. Joshi AD, Parsons DW, Velculescu VE, Riggins GJ (2011) Sodium ion channel mutations in glioblastoma patients correlate with shorter survival. Mol Cancer 10:17

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  57. Cuddapah VA, Turner KL, Seifert S, Sontheimer H (2013) Bradykinin-induced chemotaxis of human gliomas requires the activation of KCa3.1 and ClC-3. J Neurosci 33:1427–1440

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  58. Palani M, Arunkumar R, Janardhanam VAPD (2010) Biochemical and cytogenetic analysis of brain tissues in different grades of glioma patients. Ann Neurosci 17:120–125

    Article  PubMed Central  PubMed  Google Scholar 

  59. Kislin KL, McDonough WS, Eschbacher JM, Armstrong BA, Berens ME (2009) NHERF-1: modulator of glioblastoma cell migration and invasion. Neoplasia 11:377–387

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  60. Zhu SJ, Wang KJ, Gan SW, Xu J, Xu SY, Sun SQ (2013) Expression of aquaporin8 in human astrocytomas: correlation with pathologic grade. Biochem Biophys Res Commun 440:168–172

    Article  CAS  PubMed  Google Scholar 

  61. El Hindy N, Bankfalvi A, Herring A, Adamzik M, Lambertz N, Zhu Y, Siffert W, Sure U, Sandalcioglu IE (2013) Correlation of aquaporin-1 water channel protein expression with tumor angiogenesis in human astrocytoma. Anticancer Res 33:609–613

    PubMed  Google Scholar 

  62. Di Cristofori A, Carrabba G, Lanfranchi G, Menghetti C, Rampini P, Caroli M (2013) Continuous tamoxifen and dose-dense temozolomide in recurrent glioblastoma. Anticancer Res 33(8):3383–3389

    Google Scholar 

Download references

Acknowledgments

The authors thank Ms. Heike Blum for illustration design and artwork.

Author information

Authors and Affiliations

  1. Department of Neurology, University of Münster, Albert-Schweitzer-Campus 1, 48149, Münster, Germany

    Ole J. Simon, Thomas Müntefering, Oliver M. Grauer & Sven G. Meuth

Authors
  1. Ole J. Simon
    View author publications

    You can also search for this author inPubMed Google Scholar

  2. Thomas Müntefering
    View author publications

    You can also search for this author inPubMed Google Scholar

  3. Oliver M. Grauer
    View author publications

    You can also search for this author inPubMed Google Scholar

  4. Sven G. Meuth
    View author publications

    You can also search for this author inPubMed Google Scholar

Corresponding author

Correspondence to Ole J. Simon.

Ethics declarations

Conflict of interest

The authors declare no conflicts of interests.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Simon, O.J., Müntefering, T., Grauer, O.M. et al. The role of ion channels in malignant brain tumors. J Neurooncol 125, 225–235 (2015). https://doi.org/10.1007/s11060-015-1896-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11060-015-1896-9

Keywords