Glioblastoma is the most common primary brain tumor with the most dismal prognosis. It is characterized by extensive invasion, migration, and angiogenesis. Median survival is only 15 months due to this behavior, rendering focal surgical resection ineffective and adequate radiotherapy impossible. At this moment, several ion channels have been implicated in glioblastoma proliferation, migration, and invasion. This paper summarizes studies on potassium, sodium, chloride, and calcium channels of glioblastoma. It provides an up-to-date overview of the literature that could ultimately lead to new therapeutic targets. 1. Introduction Glioblastoma (astrocytomas, WHO grade IV) is the most aggressive primary brain tumor. With an incidence of 3.5 per 100,000 people per year, it may affect children, adults, and elderly. However, it preferentially affects adults between 45 and 75 years of age [1]. Glioblastomas can either present themselves as primary glioblastomas (95%), which manifest de novo and lack precursor tumors, or secondary glioblastomas. These tumors have progressed from less malignant glioma [2]. Surgery is the initial intervention when a patient has been diagnosed with a brain tumor. This is needed to obtain a histological diagnosis and reduces the space-occupying effect of the tumor. However, in glioblastoma, surgery is of limited therapeutic value, as complete resection is impossible due to the extensive invasive, and migratory behavior of glioblastoma cells. This renders radiotherapy ineffective as well. The current treatment is concomitant administration of temozolomide and radiotherapy. However, median survival is only 15 months [3]. The understanding of molecular alterations in signaling pathways and the consequent pathology in glioblastoma has greatly increased in the last years due to the availability of new techniques, such as genome-wide sequencing. One of the pathways that are frequently affected in glioblastoma includes channels involved in transport of sodium, potassium, and calcium ions [4]. The present paper provides an overview of the current evidence of the involvement of these ion channels in glioblastoma in terms of gliomagenesis, glioma progression, and their effect on prognosis. Because of the progression of lower-grade glioma to glioblastoma, the involvement of ion channels in high-grade glioma is discussed as well. Finally, the application of these insights is discussed in the light of future prospects for experimental and clinical practice. 2. Ion Channels and Glioblastoma Glial cells express a variety of ion channels [5].
References
[1]
D. N. Louis, H. Ohgaki, O. D. Wiestler et al., “The 2007 WHO classification of tumours of the central nervous system,” Acta Neuropathologica, vol. 114, no. 2, pp. 97–109, 2007.
[2]
H. Ohgaki and P. Kleihues, “Genetic pathways to primary and secondary glioblastoma,” American Journal of Pathology, vol. 170, no. 5, pp. 1445–1453, 2007.
[3]
R. Stupp, W. P. Mason, M. J. Van Den Bent et al., “Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma,” New England Journal of Medicine, vol. 352, no. 10, pp. 987–996, 2005.
[4]
D. W. Parsons, S. Jones, X. Zhang et al., “An integrated genomic analysis of human glioblastoma multiforme,” Science, vol. 321, no. 5897, pp. 1807–1812, 2008.
[5]
A. Verkhratsky and C. Steinh？user, “Ion channels in glial cells,” Brain Research Reviews, vol. 32, no. 2-3, pp. 380–412, 2000.
[6]
D. J. Blackiston, K. A. McLaughlin, and M. Levin, “Bioelectric controls of cell proliferation: ion channels, membrane voltage and the cell cycle,” Cell Cycle, vol. 8, no. 21, pp. 3519–3528, 2009.
[7]
A. K. Weaver, X. Liu, and H. Sontheimer, “Role for calcium-activated potassium channels (BK) in growth control of human malignant glioma cells,” Journal of Neuroscience Research, vol. 78, no. 2, pp. 224–234, 2004.
[8]
S. Ishiuchi, K. Tsuzuki, Y. Yoshida et al., “Blockage of Ca2+-permeable AMPA receptors suppresses migration and induces apoptosis in human glioblastoma cells,” Nature Medicine, vol. 8, no. 9, pp. 971–978, 2002.
[9]
V. C. H. Lui, S. S. S. Lung, J. K. S. Pu, K. N. Hung, and G. K. K. Leung, “Invasion of human glioma cells is regulated by multiple chloride channels including ClC-3,” Anticancer Research, vol. 30, no. 11, pp. 4515–4524, 2010.
[10]
L. Soroceanu, T. J. Manning Jr., and H. Sontheimer, “Modulation of glioma cell migration and invasion using Cl- and K+ ion channel blockers,” Journal of Neuroscience, vol. 19, no. 14, pp. 5942–5954, 1999.
[11]
R. Wondergem and J. W. Bartley, “Menthol increases human glioblastoma intracellular Ca2+, BK channel activity and cell migration,” Journal of Biomedical Science, vol. 16, no. 1, article no. 90, 2009.
[12]
R. Wondergem, T. W. Ecay, F. Mahieu, G. Owsianik, and B. Nilius, “HGF/SF and menthol increase human glioblastoma cell calcium and migration,” Biochemical and Biophysical Research Communications, vol. 372, no. 1, pp. 210–215, 2008.
[13]
S. S. Kang, K. S. Han, B. M. Ku et al., “Caffeine-mediated inhibition of calcium release channel inositol 1,4,5-trisphosphate receptor subtype 3 blocks glioblastoma invasion and extends survival,” Cancer Research, vol. 70, no. 3, pp. 1173–1183, 2010.
[14]
D. Basrai, R. Kraft, C. Bollensdorff, L. Liebmann, K. Benndorf, and S. Patt, “BK channel blockers inhibit potassium-induced proliferation of human astrocytoma cells,” NeuroReport, vol. 13, no. 4, pp. 403–407, 2002.
[15]
A. K. Weaver, V. C. Bomben, and H. Sontheimer, “Expression and function of calcium-activated potassium channels in human glioma cells,” GLIA, vol. 54, no. 3, pp. 223–233, 2006.
[16]
C. B. Ransom and H. Sontheimer, “BK channels in human glioma cells,” Journal of Neurophysiology, vol. 85, no. 2, pp. 790–803, 2001.
[17]
C. B. Ransom, X. Liu, and H. Sontheimer, “BK channels in human glioma cells have enhanced calcium sensitivity,” GLIA, vol. 38, no. 4, pp. 281–291, 2002.
[18]
X. Liu, Y. Chang, P. H. Reinhart, and H. Sontheimer, “Cloning and characterization of glioma BK, a novel BK channel isoform highly expressed in human glioma cells,” Journal of Neuroscience, vol. 22, no. 5, pp. 1840–1849, 2002.
[19]
I. F. Abdullaev, A. Rudkouskaya, A. A. Mongin, and Y. H. Kuo, “Calcium-activated potassium channels BK and IK1 are functionally expressed in human gliomas but do not regulate cell proliferation,” PLoS One, vol. 5, no. 8, Article ID e12304, 2010.
[20]
A. K. Weaver, M. L. Olsen, M. B. McFerrin, and H. Sontheimer, “BK channels are linked to inositol 1,4,5-triphosphate receptors via lipid rafts: a novel mechanism for coupling [Ca2+]i to ion channel activation,” Journal of Biological Chemistry, vol. 282, no. 43, pp. 31558–31568, 2007.
[21]
A. Bordey and H. Sontheimer, “Electrophysiological properties of human astrocytic tumor cells in situ: enigma of spiking glial cells,” Journal of Neurophysiology, vol. 79, no. 5, pp. 2782–2793, 1998.
[22]
E. A. Newman, “Inward-rectifying potassium channels in retinal glial (Muller) cells,” Journal of Neuroscience, vol. 13, no. 8, pp. 3333–3345, 1993.
[23]
M. L. Olsen and H. Sontheimer, “Mislocalization of Kir channels in malignant glia,” GLIA, vol. 46, no. 1, pp. 63–73, 2004.
[24]
R. K. Orkand, J. G. Nicholls, and S. W. Kuffler, “Effect of nerve impulses on the membrane potential of glial cells in the central nervous system of amphibia,” Journal of Neurophysiology, vol. 29, no. 4, pp. 788–806, 1966.
[25]
S. F. Traynelis and R. Dingledine, “Potassium-induced spontaneous electrographic seizures in the rat hippocampal slice,” Journal of Neurophysiology, vol. 59, no. 1, pp. 259–276, 1988.
[26]
Z. C. Ye and H. Sontheimer, “Glioma cells release excitotoxic concentrations of glutamate,” Cancer Research, vol. 59, no. 17, pp. 4383–4391, 1999.
[27]
S. Patt, K. Preu？at, C. Beetz et al., “Expression of ether à go-go potassium channels in human gliomas,” Neuroscience Letters, vol. 368, no. 3, pp. 249–253, 2004.
[28]
A. Masi, A. Becchetti, R. Restano-Cassulini et al., “hERG1 channels are overexpressed in glioblastoma multiforme and modulate VEGF secretion in glioblastoma cell lines,” British Journal of Cancer, vol. 93, no. 7, pp. 781–792, 2005.
[29]
E. Lastraioli, L. Guasti, O. Crociani et al., “herg1 gene and HERG1 protein are overexpressed in colorectal cancers and regulate cell invasion of tumor cells,” Cancer Research, vol. 64, no. 2, pp. 606–611, 2004.
[30]
A. Cherubini, G. L. Taddei, O. Crociani et al., “HERG potassium channels are more frequently expressed in human endometrial cancer as compared to non-cancerous endometrium,” British Journal of Cancer, vol. 83, no. 12, pp. 1722–1729, 2000.
[31]
S. Pillozzi, M. F. Brizzi, M. Balzi et al., “HERG potassium channels are constitutively expressed in primary human acute myeloid leukemias and regulate cell proliferation of normal and leukemic hemopoietic progenitors,” Leukemia, vol. 16, no. 9, pp. 1791–1798, 2002.
[32]
S. Godard, G. Getz, M. Delorenzi et al., “Classification of human astrocytic gliomas on the basis of gene expression: a correlated group of genes with angiogenic activity emerges as a strong predictor of subtypes,” Cancer Research, vol. 63, no. 20, pp. 6613–6625, 2003.
[33]
M. L. Olsen, S. Schade, S. A. Lyons, M. D. Amaral, and H. Sontheimer, “Expression of voltage-gated chloride channels in human glioma cells,” Journal of Neuroscience, vol. 23, no. 13, pp. 5572–5582, 2003.
[34]
B. Fioretti, E. Castigli, I. Calzuola, A. A. Harper, F. Franciolini, and L. Catacuzzeno, “NPPB block of the intermediate-conductance Ca2+-activated K+ channel,” European Journal of Pharmacology, vol. 497, no. 1, pp. 1–6, 2004.
[35]
V. A. Cuddapah and H. Sontheimer, “Molecular interaction and functional regulation of ClC-3 by Ca2+/calmodulin-dependent protein kinase II (CaMKII) in human malignant glioma,” Journal of Biological Chemistry, vol. 285, no. 15, pp. 11188–11196, 2010.
[36]
A. Bordey, H. Sontheimer, and J. Trouslard, “Muscarinic activation of BK channels induces membrane oscillations in glioma cells and leads to inhibition of cell migration,” Journal of Membrane Biology, vol. 176, no. 1, pp. 31–40, 2000.
[37]
IARC, Agents Classified by the IARC Monographs, vol. 1–102, IARC, 2011.
[38]
X. Ding, Z. He, K. Zhou et al., “Essential role of trpc6 channels in G2/M phase transition and development of human glioma,” Journal of the National Cancer Institute, vol. 102, no. 14, pp. 1052–1068, 2010.
[39]
A. D. Joshi, D. W. Parsons, V. E. Velculescu, and G. J. Riggins, “Sodium ion channel mutations in glioblastoma patients correlate with shorter survival,” Molecular Cancer, vol. 10, article 17, 2011.
[40]
H. Yan, D. W. Parsons, G. Jin et al., “IDH1 and IDH2 mutations in gliomas,” New England Journal of Medicine, vol. 360, no. 8, pp. 765–773, 2009.
[41]
G. G. Goldin and A. R. Safa, “Digitalis and cancer,” Lancet, vol. 1, no. 8386, p. 1134, 1984.
[42]
T. Mijatovic, E. Van Quaquebeke, B. Delest, O. Debeir, F. Darro, and R. Kiss, “Cardiotonic steroids on the road to anti-cancer therapy,” Biochimica et Biophysica Acta, vol. 1776, no. 1, pp. 32–57, 2007.
[43]
J. K. T. Wang, S. Portbury, M. B. Thomas et al., “Cardiac glycosides provide neuroprotection against ischemic stroke: discovery by a brain slice-based compound screening platform,” Proceedings of the National Academy of Sciences of the United States of America, vol. 103, no. 27, pp. 10461–10466, 2006.
[44]
J. K. Bubien, D. A. Keeton, C. M. Fuller et al., “Malignant human gliomas express an amiloride-sensitive Na+ conductance,” American Journal of Physiology, vol. 276, no. 6, pp. C1405–C1410, 1999.
[45]
J. K. Bubien, H. L. Ji, G. Y. Gillespie et al., “Cation selectivity and inhibition of malignant glioma Na+ channels by Psalmotoxin 1,” American Journal of Physiology, vol. 287, no. 5, pp. C1282–C1291, 2004.
[46]
Y. Chen and S. H. Tseng, “The potential of tetrandrine against gliomas,” Anti-Cancer Agents in Medicinal Chemistry, vol. 10, no. 7, pp. 534–542, 2010.
[47]
Y. Chen, J. C. Chen, and S. H. Tseng, “Tetrandrine suppresses tumor growth and angiogenesis of gliomas in rats,” International Journal of Cancer, vol. 124, no. 10, pp. 2260–2269, 2009.
[48]
R. G. W. Verhaak, K. A. Hoadley, E. Purdom et al., “Integrated genomic analysis identifies clinically relevant subtypes of glioblastoma characterized by abnormalities in PDGFRA, IDH1, EGFR, and NF1,” Cancer Cell, vol. 17, no. 1, pp. 98–110, 2010.
[49]
N. S. Ningaraj, U. T. Sankpal, D. Khaitan, E. A. Meister, and T. Vats, “Activation of KATP channels increases anticancer drug delivery to brain tumors and survival,” European Journal of Pharmacology, vol. 602, no. 2-3, pp. 188–193, 2009.
[50]
A. Li, J. Walling, Y. Kotliarov et al., “Genomic changes and gene expression profiles reveal that established glioma cell lines are poorly representative of primary human gliomas,” Molecular Cancer Research, vol. 6, no. 1, pp. 21–30, 2008.
[51]
J. Clarke, N. Butowski, and S. Chang, “Recent advances in therapy for glioblastoma,” Archives of Neurology, vol. 67, no. 3, pp. 279–283, 2010.
