Molecular Neurobiology

, Volume 42, Issue 1, pp 89–96

Glioma Cell Death: Cell–Cell Interactions and Signalling Networks

  • H. Anne Leaver
  • Maria Theresa Rizzo
  • Ian R. Whittle
Article

Abstract

The prognosis for patients with malignant gliomas is poor, but improvements may emerge from a better understanding of the pathophysiology of glioma signalling. Recent therapeutic developments have implicated lipid signalling in glioma cell death. Stress signalling in glioma cell death involves mitochondria and endoplasmic reticulum. Lipid mediators also signal via extrinsic pathways in glioma cell proliferation, migration and interaction with endothelial and microglial cells. Glioma cell death and tumour regression have been reported using polyunsaturated fatty acids in animal models, human ex vivo explants, glioma cell preparations and in clinical case reports involving intratumoral infusion. Cell death signalling was associated with generation of reactive oxygen intermediates and mitochondrial and other signalling pathways. In this review, evidence for mitochondrial responses to stress signals, including polyunsaturated fatty acids, peroxidising agents and calcium is presented. Additionally, evidence for interaction of glioma cells with primary brain endothelial cells is described, modulating human glioma peroxidative signalling. Glioma responses to potential therapeutic agents should be analysed in systems reflecting tumour connectivity and CNS structural and functional integrity. Future insights may also be derived from studies of signalling in glioma-derived tumour stem cells.

Keyword

Glioma Cell death signalling Mitochondria 

Abbreviations

AA

arachidonic acid

Akt

serine–threonine protein kinase

CHOP/GADD153

CCAAT/enhancer binding protein homologous transcription factor

CNS

central nervous system

COX

cyclo-oxygenase

ΔΨm

transmembrane mitochondrial potential

ER

endoplasmic reticulum

ERK

extracellular signal-regulated kinase

GLA

gamma linolenic acid

GF

growth factors

GFAP

glial fibrillary acidic protein

GRP78/BiP

ER glucose-regulated protein 78

H2O2

hydrogen peroxide

iNOS

inducible nitric oxide synthetase

LO

lipoxygenase

MEK-1/2

mitogen-activated protein kinase kinase 1/2

MPT

mitochondrial permeability transition pore

PARP

pol(ADP-ribosyl) polymerase

PBR

peripheral benzodiazepine receptor

PDGF

platelet-derived growth factor

PDR

peripheral benzodiazepine receptor

Plase A2

phospholipase A2

PKAII

type II protein kinase A

PUFA

polyunsaturated fatty acids

roi

reactive oxygen intermediates

TLR

Toll-like receptor-2

TNF

tumour necrosis factor

TRAIL

TNF-related apoptosis-inducing ligand

roi

reactive oxygen intermediates

VEGFR

vascular endothelial cell growth factor receptor

References

  1. 1.
    Anderson E, Grant R, Lewis SC, Whittle IR (2008) Randomised phase III controlled trials of therapy in malignant glioma: where are we after 40 years? Br J Neurosurg 22:339–349CrossRefPubMedGoogle Scholar
  2. 2.
    Colquhoun A (2010) Lipids, mitochondria and cell death: implications in neuro-oncology. Mol Neurobiol special edition Cell Death Signalling. doi:10.1007/s12035-010-8134-4
  3. 3.
    Piccirillo SGM, Combi R, Cajola L, Patrizi A, Redaelli S, Bentivegna A, Baronchelli S, Maira G, Pollo B, Mangiola A, DiMeco F, Dalprà L, Vescovi AL (2009) Distinct pools of cancer stem-like cells coexist within human glioblastomas and display different tumorigenicity and independent genomic evolution. Oncogene 28:1807–1811CrossRefPubMedGoogle Scholar
  4. 4.
    Evans SM, Judy KD, Dunphy I, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins WT, Hwang WT, Nelson PT, Lustig RA, Jenkins K, Magarelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumours. Clin Cancer Res 10:8177–8184CrossRefPubMedGoogle Scholar
  5. 5.
    Camandola S, Poli G, Mattson MP (2000) Lipid peroxidation product, 4-hydroxy NE, increases AP-1 binding through caspase activity in neurones. J Neurochem 74:159–165CrossRefPubMedGoogle Scholar
  6. 6.
    Colquhoun A (2002) GLA alters the composition of mitochondrial subfractions, decreases outer mitochondrial binding of hexokinase and alters carnitine palitoyltransferase I properties in Walker 256 rat tumour. Biochim Biophys Acta 1583:74–84PubMedGoogle Scholar
  7. 7.
    Coyle JT, Puttfarken P (1993) Oxidative stress, glutamate and neurodegenerative disorders. Science 262:689–695CrossRefPubMedGoogle Scholar
  8. 8.
    Curtin JF, Liu N, Candolfi M, Xiong W, Assi H, Yagiz K, Edwards MR, Michelsen KS, Kroeger KM, Liu C, Muhammad AKMG, Clark MC, Arditi M, Comin-Anduix B, Ribas A, Lowenstein PR, Castro MG (2009) HMGB1 mediates endogenous TLR2 activation and brain tumour regression. PLoS Med 6:e-1000010CrossRefGoogle Scholar
  9. 9.
    Falsig J, Markus L, Leist M (2004) Defined inflammatory states in astrocyte cultures: correlation with susceptibility towards CD95-driven apoptosis. J Neurochem 88:181–193PubMedCrossRefGoogle Scholar
  10. 10.
    Graeber TG, Osmanian C, Jacks T, Houseman DE, Koch CJ, Lowe SW, Giaccia AJ (1996) Hypoxia-mediated selection of cells with diminished apoptotic potential in solid tumours. Nature; 379:88–91CrossRefPubMedGoogle Scholar
  11. 11.
    Higuchi Y, Yoshimoto T (2002) AA converts glutathione depletion into necrosis by promoting lipid peroxidation in rat glioma cells. Arch Biochem Biophys 400:133–140CrossRefPubMedGoogle Scholar
  12. 12.
    Jenkins K, Mararelli DP, Hahn SM, Collins RA, Grady MS, Koch CJ (2004) Hypoxia is important in the biology and aggression of human glial brain tumours. Clin Cancer Res 10:8177–8184CrossRefPubMedGoogle Scholar
  13. 13.
    Jeremias I, Steiner HH, Benner A, Debatin KM, Herold-Mende C (2004) Cell death induction by betulinic acid, ceramide and TRAIL in primary glioblastoma multiforme cells. Acta Neurochir 146:721–729CrossRefGoogle Scholar
  14. 14.
    Kardosh A, Golden EB, Pyrko P, Uddin J, Hofman FM, Chen TC, Louie SG, Petasis NA, Schönthal AH (2008) Aggravated endoplasmic reticulum stress as a basis for enhanced glioblastoma cell killing by bortezomib in combination with celecoxib or its non-coxib analogue, 2,5-dimethyl–celecoxib. Cancer Res 68:843–851CrossRefPubMedGoogle Scholar
  15. 15.
    Keller JN, Mark RJ, Bruce AJ, Blanc E, Rothstein JD, Uchida K, Waeg G, Mattson MP (1997) 4-Hydoxynonetal, an aldehydic product of lipid peroxidation, impairs glutamate transport and mitochondrial function in synaptosomes. Neuroscience 80:685–696CrossRefPubMedGoogle Scholar
  16. 16.
    Kiebish MA, Han X, Cheng H, Chuang JH, Seyfried TN. Brain mitochondrial lipid abnormalities in mice susceptible to spontaneous glioma. Lipids;43:951–959Google Scholar
  17. 17.
    Koritzinsky M, Magagnin MG, van den Beucken T, Seigneuric R, Savelkouls K, Dostie J, Pyronnet S, Kaufman RJ, Weppler SA, Voncken JW, Lambin P, Koumenis C, Sonenberg N, Bradly G, Wouters BG (2006) Gene expression during acute and prolonged hypoxia is regulated by distinct mechanisms of translational control. EMBO J 25:1114–1125CrossRefPubMedGoogle Scholar
  18. 18.
    Leaver HA, Williams JR, CraiG SR, Gregor A, Ironside JW, Whittle IR, Yap PL (1997) Network analysis of arachidonic acid pathophysiology in human phagocytes and primary brain tumours. Ann NY Acad Sci 832:200–214CrossRefPubMedGoogle Scholar
  19. 19.
    Leaver HA, Williams JR, Gregor A, Ironside JW, Miller EP, Su BH, Prescott RJ, Whittle IR (1999) Dynamics of reactive oxygen intermediate production by human brain tumours: n-6 essential fatty acid effects. Eur J Clin Invest 29:220–231CrossRefPubMedGoogle Scholar
  20. 20.
    Leaver HA, Williams JR, Smith C, Whittle IR (2004) Intracellular oxidation by human glioma cell populations: effect of arachidonic acid. Prostagl Leukot Essent Fatty Acids 70:449–453CrossRefGoogle Scholar
  21. 21.
    Lee YW, Ha MS, Kim YK (2001) H2O2-induced cell death in human glioma cells: role of lipid peroxidation and PARP activation. Neurochem Res 26:337–342CrossRefPubMedGoogle Scholar
  22. 22.
    Lee WC, Choi CH, Cha SH, Oh HY, Kim YK (2005) Role of ERK in hydrogen peroxide induced cell death in human glioma cells. Neurochem Res 30:263–270CrossRefPubMedGoogle Scholar
  23. 23.
    Malagarie-Canenave S, Andrie-Abadie N, Segul B, Gouaze V, Tardy C, Cuvillier O, Levade T (2002) Sphingolipid signalling: molecular basis and role in TNFα signalling. Rev Mol Med 4:1–15Google Scholar
  24. 24.
    Marangolo M, McGee MM, Tipton KF, Williams DC, Zisterer DM (2009) Oxidative stress induces apoptosis in C6 glioma cells: involvement of MAP kinases and NfκB. Neurotox Res 3:397–409CrossRefGoogle Scholar
  25. 25.
    Renschler MF (2004) The emerging role of reactive oxygen species in cancer therapy. Eur J Cancer 40:1934–1940CrossRefPubMedGoogle Scholar
  26. 26.
    Rush GF, Khan S, Bamisaiye G, Bidwell P, Leaver HA, Rizzo MT (2007) c-jun amin-terminal kinase and mitogen activated protein kinase mediate hepatocyte growth factor-induced migration of brain endothelial cells. Exper Cell Res 313:121–132CrossRefGoogle Scholar
  27. 27.
    Watjen W, Beyersman D (2004) Cadmium induced apoptosis in C6 glioma cells: influence of oxidative stress. Biometals 17:65–78CrossRefPubMedGoogle Scholar
  28. 28.
    Wu Y, Zhang H, Dong Y, Park YM, Ip C (2005) Endoplasmic reticulum stress signal mediators are targets of selenium action. Cancer Res 65:9073–9079CrossRefPubMedGoogle Scholar
  29. 29.
    Yoshida S, Busto R, Watson BD, Santiso M, Ginsberg MD (2006) Postischemic cerebral lipid peroxidation in vitro. J Neurochem 44:1593–1601CrossRefGoogle Scholar
  30. 30.
    Bazán NG (1976) Free arachidonic acid and other lipids in the nervous system during early ischemia and after electroshock. Adv Exp Med Biol 72:317–335PubMedGoogle Scholar
  31. 31.
    Lukiw WJ, Bazan NG (2010) Inflammatory, apoptotic and survival gene signalling in Alzheimer’s disease Mol Neurobiol special edition: Cell Death. doi:10.1007/s12035-010-8126-4
  32. 32.
    Meves H (2008) Arachidonic acid and ion channels: an update. Br J Pharmacol 155:4–16CrossRefPubMedGoogle Scholar
  33. 33.
    Payner T, Leaver HA, Knapp B, Whittle IR, Trifan OC, Miller S, Rizzo MT (2006) Microsomal prostaglandin E synthase-1 regulates human glioma cell growth via prostaglandin E2-dependent activation of type II protein kinase A. Mol Cancer Ther 5:1817–1826CrossRefPubMedGoogle Scholar
  34. 34.
    Rizzo MT, Pudlo N, Farrell L, Leaver HA (2002) Specificity of arachidonic acid-induced inhibition of growth and activation of c-jun kinases and p38 mitogen-activated protein kinase in hemaptopietic cells. Prostagl, Leucotr Essen Fatty Acids 66:31–40CrossRefGoogle Scholar
  35. 35.
    Rizzo MT, Leaver HA, Yu WM, Kovacs RJ (1999) Arachidonic acid induces mobilization of calcium stores and c-jun gene expression: evidence that intracellular calcium release is associated with c-jun. Prostagl Leucotr Essen Fatty Acids 60:187–198CrossRefGoogle Scholar
  36. 36.
    Wake H, Moorhouse AJ, Jinno S, Kohsaka S, Nabekura J (2009) Resting microglia directly monitor functional state of synapses in vivo and determine the fate of ischemic terminals. J Neurosci 29:3974–3980CrossRefPubMedGoogle Scholar
  37. 37.
    Bell HS, Wharton SB, Leaver HA, Whittle IR (1999) Effects of n-6 essential fatty acids on glioma invasion and growth: experimental studies using human and rodent glioma spheroids in collagen gels. J Neurosurg 91:989–998CrossRefPubMedGoogle Scholar
  38. 38.
    Chan PH, Fishman RA (1982) Alterations in membrane integrity and cellular constituents in neuroblastoma and glioma cells. Brain Res 248:151–157CrossRefPubMedGoogle Scholar
  39. 39.
    Vartak S, Robbins MEC, Spector AA (1997) Polyunsaturated fatty acids increase the sensitivity of 36B10 rat astrocytoma cells to radiation-induced cell kill. Lipids 32:283–292CrossRefPubMedGoogle Scholar
  40. 40.
    Das UN (2004) From the bench to the clinic: GLA therapy of human glioma. Prostaglandins Leukot Essent Fatty Acids 70:539–552CrossRefPubMedGoogle Scholar
  41. 41.
    Leaver HA, Bell HS, Rizzo MT, Ironside JW, Gregor A, Wharton S, Whittle IR (2002) Anti-tumour and pro-apoptotic actions of highly unsaturated fatty acids in glioma. Prostaglandins, Leucot Essent Fatty Acids 66:19–29CrossRefGoogle Scholar
  42. 42.
    Leaver HA, Wharton S, Bell HS, Whittle IR (2002) Highly unsaturated fatty acid induced tumour regression in experimental glioma: pharmacodynamics and bioavailability of a novel anti-tumour agent, gamma linolenic acid, in an implantation glioma model: effects on tumour biomass, apoptosis and normal neuronal tissue. Prostagl, Leucotr Essen Fatty Acids 67:283–292CrossRefGoogle Scholar
  43. 43.
    Llado V, Gutierrez A, Martinez J, Casas J, Teres S, Higuera M, Galmes A, Saus C, Busquets X, Escriba PV (2008) Minerval induces apoptosis in jurkat and other cancer cells. J Cell Mol Med “postprint”; doi:10.1111/j.1582-4934.2008.00625.x
  44. 44.
    Serini S, Piccioni E, Merendino N, Calviello G (2009) Dietary polyunsaturated fatty acids as inducers of apoptosis: implications for cancer. Apoptosis 14:135–152CrossRefPubMedGoogle Scholar
  45. 45.
    Williams JR, Leaver HA, Ironside JW, Gregor A, Miller EP, Whittle IR (1998) Apoptosis in human gliomas: actions of arachidonic acid. Prostagl, Leucotr Essen Fatty Acids 58:193–200CrossRefGoogle Scholar
  46. 46.
    Zhang J, Shipston MJ, Brown S (2010) A role for potassium permeability in the recognition, clearance and anti-inflammatory effects of apoptotic cells. Mol Neurobiol: special edition Cell Death Signalling. doi:10.1007/s12035-010-8127-3
  47. 47.
    Wyllie AH (2010) Where, O Death, Is Thy Sting? A brief review of apoptosis biology, Molecular Neurobiology special edition Cell Death Signalling. doi:10.1007/s12035-010-8125-5 Google Scholar
  48. 48.
    Ordys BB, Launay S, Deighton RF, McCulloch J, Whittle IR (2010) The role of Mitochondria in Glioma pathophysiology. Mol Neurobiol special edition. Cell Death Signalling. doi:10.1007/s12035-010-8133-5
  49. 49.
    Rizzo MT, Leaver A (2010) Brain endothelial cell death: modes, signalling, pathways and relevance to neural development, homeostasis and disease. Mol Neurobiol special edition Cell Death Signalling. doi:10.1007/s12035-010-8132-6
  50. 50.
    Mitchell P (1961) Coupling of phosphorylation to electron and hydrogen transfer by a chemi-osmotic type of mechanism. Nature 191:144–148CrossRefPubMedGoogle Scholar
  51. 51.
    Michell RH (1975) Inositol lipids and cell surface receptor function. Bichem Biophys Acta 415:81–147Google Scholar
  52. 52.
    Jacobson J, Duchen MR (2002) Mitochondrial oxidative stress and cell death in astrocytes—requirement for stored Ca2+ and sustained opening of the permeability pore. J Cell Sci 115:1175–1188PubMedGoogle Scholar
  53. 53.
    Parnas M, Katz B, Lev S, Tzarfaty V, Dadon D, Shaag G, Metzner H, Yaka R, Minke B (2009) Membrane lipid modulations remove divalent open channel block from TRP-like and NMDA channels. J Neurosci 29:2371–2383CrossRefPubMedGoogle Scholar
  54. 54.
    Kerr JFR, Wyllie AH, Currie AR (1972) Apoptosis: a basic biological phenomenon with wide-ranging implications in tissue kinetics. Br J Cancer 26:239–257PubMedGoogle Scholar
  55. 55.
    Chang CJ, Hsu CC, Yung MC, Chen KY, Tzao C, Wu WF, Chou HY, Lee YY, Lu KH, Chiou SH, Ma HI (2009) Enhanced radiosensitivity and radiation-induced apoptosis in glioma CD133-positive cells by knockdown of SirT1 expression. Biochem Biophys Res Comm 380:236–242CrossRefPubMedGoogle Scholar
  56. 56.
    Garcia-Escudero V, Gargini R, Izquierdo M (2008) Glioma regression in vitro and in vivo by a suicide combined treatment. Mol Canc Res 6:407–417CrossRefGoogle Scholar
  57. 57.
    Horrobin DF (1979) Schizophrenia: reconciliation of the dopamine, prostaglandin, and opioid concepts and the role of the pineal. Lancet 313(8115):529–531CrossRefGoogle Scholar
  58. 58.
    Yacoub A, Gupta P, Park MA, Rhamani M, Hamed H, Hanna D, Zhang G, Sarkar D, Lebedeva IV, Emdad L, Koumenis C, Curiel DT, Grant S, Fisher PB, Dent P (2008) Regulation of GST-MDA-7 toxicity in human glioblastoma cells by ERBB1, ERK1/2, PI3K, and JNK1-3 pathway signaling. Mol Cancer Ther 7:314–329CrossRefPubMedGoogle Scholar
  59. 59.
    Yacoub A, Mitchell C, Hong Y, Gopalkrishnan RV, Su ZZ, Gupta P, Sauane M, Lebedeva IV, Curiel DT, Mahasreshti PJ, Rosenfeld MR, Broaddus WC, James CD, Grant S, Fisher PB, Dent P (2004) MDA-7 regulates cell growth and radiosensitivity in vitro of primary (non-established) human glioma cells. Cancer Biol Ther 8:739–751Google Scholar
  60. 60.
    Ma Y, Yuan R, Fan S, Hu C, Goldberg ID, Laterra JJ, Rosen EM (2006) Identification of genes that modulate sensitivity of U373MG glioblastoma cells to cis-platinum. Anticancer Drugs 17:733–751CrossRefPubMedGoogle Scholar
  61. 61.
    Liao H, Duka T, Teng FYH, Sun L, Bu W, Ahmed S, Tang BL, Xiao Z (2004) Nogo-66 and myelin-associated glycoprotein (MAG) inhibit the adhesion and migration of Nogo-66 receptor expressing human glioma cells. J Neurochem 90:1156–1162CrossRefPubMedGoogle Scholar
  62. 62.
    Chelli B, Lena A, Vanacore R, Pozzo E, Costa B, Rossi L, Salvetti A, Scatena F, Ceruti S, Abbracchio MP, Gremigni V, Martini C (2004) Peripheral benzodiazepine receptor ligands: mitochondrial transmembrane potential depolarisation and apoptosis in rat C6 glioma. Biochem Pharmacol 68:125–134CrossRefPubMedGoogle Scholar
  63. 63.
    Bell HS, Whittle IR, Walker M, Leaver HA, Wharton SB (2001) Development of necrosis and apoptosis in glioma: experimental findings using spheroid culture systems. Neuropathol Appl Neurobiol 27:291–304CrossRefPubMedGoogle Scholar
  64. 64.
    Bian XW, Jiang XF, Chen JH, Bai JS, Dai C, Quing-Liang W, Lu JY, Zhao W, Xin R, Liu MY, Shi JQ, Ji MW (2006) Increased angiogenesis capabilities of endothelial cells from microvessels of malignant human glioma. Int Immunopharm 6:90–99CrossRefGoogle Scholar
  65. 65.
    Hurst RD, Fritz IB (1996) Properties of an immortalised vascular endothelial/glioma cell co-culture model on the blood–brain barrier. J Cell Physiol 167:81–88CrossRefPubMedGoogle Scholar
  66. 66.
    Norden AD, Drappatz J, Wen PY (2008) Novel anti-angiogenic therapies for malignant gliomas. Lancet Neurol 7:1152–1160CrossRefPubMedGoogle Scholar
  67. 67.
    Zhuang W, Qin Z, Liang Z (2009) The role of autophagy in sensitising malignant glioma cells to radiation therapy. Acta Biochim Biophys Sin 41:341–351CrossRefPubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2010

Authors and Affiliations

  • H. Anne Leaver
    • 1
    • 2
  • Maria Theresa Rizzo
    • 3
  • Ian R. Whittle
    • 1
  1. 1.Department of Clinical NeurosciencesUniversity of EdinburghEdinburghUK
  2. 2.Cell Biology R&DSNBTS EdinburghEdinburghUK
  3. 3.Signal Transduction LaboratoryMethodist Research InstituteIndianapolisUSA

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