Potential involvement of F0F1-ATP(synth)ase and reactive oxygen species in apoptosis induction by the antineoplastic agent erucylphosphohomocholine in glioblastoma cell lines (original) (raw)

Abstract

Erucylphosphohomocholine (ErPC3, Erufosine TM ) was reported previously to induce apoptosis in otherwise highly apoptosis-resistant malignant glioma cell lines while sparing their non-tumorigenic counterparts. We also previously found that the mitochondrial 18 kDa Translocator Protein (TSPO) is required for apoptosis induction by ErPC3. These previous studies also suggested involvement of reactive oxygen species (ROS). In the present study we further investigated the potential involvement of ROS generation, the participation of the mitochondrial respiration chain, and the role of the mitochondrial F O F 1 -ATP(synth)ase in the pro-apoptotic effects of ErPC3 on U87MG and U118MG human glioblastoma cell lines. For this purpose, cells were treated with the ROS chelator butylated hydroxyanisole (BHA), the mitochondrial respiration chain inhibitors rotenone, antimycin A, myxothiazol, and the uncoupler CCCP. Also oligomycin and piceatannol were studied as inhibitors of the F O and F 1 subunits of the mitochondrial F O F 1 -ATP(synth)ase, respectively. BHA was able to attenuate apoptosis induction by ErPC3, including mitochondrial ROS generation as determined with cardiolipin oxidation, as well as collapse of the mitochondrial membrane potential (Dw m ). Similarly, we found that oligomycin attenuated apoptosis and collapse of the Dw m , normally induced by ErPC3, including the accompanying reductions in cellular ATP levels. Other inhibitors of the mitochondrial respiration chain, as well as piceatannol, did not show such effects. Consequently, our findings strongly point to a role for the F O subunit of the mitochondrial F O F 1 -ATP(synth)ase in ErPC3-induced apoptosis and dissipation of Dw m as well as ROS generation by ErPC3 and TSPO.

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References (80)

  1. Louis DN (2006) Molecular pathology of malignant gliomas. Annu Rev Pathol 1:97-117
  2. Hilgard P, Klenner T, Stekar J, Unger C (1993) Alkylphosph- ocholines: a new class of membrane-active anticancer agents. Cancer Chemother Pharmacol 32:90-95
  3. Jendrossek V, Handrick R (2003) Membrane targeted anticancer drugs: potent inducers of apoptosis and putative radiosensitisers. Curr Med Chem Anticancer Agents 3:343-353
  4. Konstantinov SM, Topashka-Ancheva M, Benner A, Berger MR (1998) Alkylphosphocholines: effects on human leukemic cell lines and normal bone marrow cells. Int J Cancer 77:778-786
  5. Jendrossek V, Erdlenbruch B, Hunold A, Kugler W, Eibl H, Lakomek M (1999) Erucylphosphocholine, a novel antineoplastic ether lipid, blocks growth and induces apoptosis in brain tumor cell lines in vitro. Int J Oncol 14:15-22
  6. Jendrossek V, Kugler W, Erdlenbruch B, Eibl H, Lang F, Lak- omek M (2001) Erucylphosphocholine-induced apoptosis in chemoresistant glioblastoma cell lines: involvement of caspase activation and mitochondrial alterations. Anticancer Res 21:3389-3396
  7. Kugler W, Veenman L, Shandalov Y, Leschiner S, Spanier I, Lakomek M, Gavish M (2008) Ligands of the mitochondrial 18 kDa translocator protein attenuate apoptosis of human glio- blastoma cells exposed to erucylphosphohomocholine. Cell Oncol 30:435-450
  8. Veenman L, Shandalov Y, Gavish M (2008) VDAC activation by the 18 kDa translocator protein (TSPO), implications for apop- tosis. J Bioenerg Biomembr 40:199-205
  9. Levin E, Premkumar A, Veenman L, Kugler W, Leschiner S, Spanier I, Weisinger G, Lakomek M, Weizman A, Snyder SH, Pasternak GW, Gavish M (2005) The peripheral-type benzodi- azepine receptor and tumorigenicity: isoquinoline binding protein (IBP) antisense knockdown in the C6 glioma cell line. Bio- chemistry 44:9924-9935
  10. Erdlenbruch B, Jendrossek V, Gerriets A, Vetterlein F, Eibl H, Lakomek M (1999) Erucylphosphocholine: pharmacokinetics, biodistribution and CNS-accumulation in the rat after intravenous administration. Cancer Chemother Pharmacol 44:484-490
  11. Kugler W, Erdlenbruch B, Ju ¨nemann A, Heinemann D, Eibl H, Lakomek M (2002) Erucylphosphocholine-induced apoptosis in glioma cells: involvement of death receptor signalling and cas- pase activation. J Neurochem 82:1160-1170
  12. Kugler W, Buchholz F, Ko ¨hler F, Eibl H, Lakomek M, Erd- lenbruch B (2005) Downregulation of Apaf-1 and caspase-3 by RNA interference in human glioma cells: consequences for eru- cylphosphocholine-induced apoptosis. Apoptosis 10:1163-1174
  13. Lemeshko VV, Kugler W (2007) Synergistic inhibition of mito- chondrial respiration by anticancer agent erucylphosphohom- ocholine and cyclosporine A. J Biol Chem 282:37303-37307
  14. Braestrup C, Squires RF (1978) Pharmacological characterization of benzodiazepine receptors in the brain. Eur J Pharmacol 48:263-270
  15. McEnery MW, Snowman AM, Trifiletti RR, Snyder SH (1992) Isolation of the mitochondrial benzodiazepine receptor: associa- tion with the voltage-dependent anion channel and the adenine nucleotide carrier. Proc Natl Acad Sci USA 89:3170-3174
  16. Veenman L, Papadopoulos V, Gavish M (2007) Channel-like functions of the 18-kDa translocator protein (TSPO): regulation of apoptosis and steroidogenesis as part of the host-defense response. Curr Pharm Des 13:2385-2405
  17. Petrosillo G, Ruggiero FM, Di Venosa N, Paradies G (2003) Decreased complex III activity in mitochondria isolated from rat heart subjected to ischemia and reperfusion: role of reactive oxygen species and cardiolipin. FASEB J 17:714-716
  18. Zeno S, Zaaroor M, Leshiner S, Veenman L, Gavish M (2009) CoCl 2 induces apoptosis via the 18 kDa Translocator Protein (TSPO) in U118MG human glioblastoma cells. Biochemistry 48:4652-4661
  19. Galluzzi L, Larochette N, Zamzami N, Kroemer G (2006) Mitochondria as therapeutic targets for cancer chemotherapy. Oncogene 25:4812-4830
  20. Orrenius S (2007) Reactive oxygen species in mitochondria- mediated cell death. Drug Metab Rev 39:443-455
  21. Jacobson MD, Burne JF, King MP, Miyashita T, Reed JC, Raff MC (1993) Bcl-2 blocks apoptosis in cells lacking mitochondrial DNA. Nature 361:365-369
  22. Marchetti P, Susin SA, Decaudin D, Gamen S, Castedo M, Hirsch T, Zamzami N, Naval J, Senik A, Kroemer G (1996) Apoptosis- associated derangement of mitochondrial function in cells lacking mitochondrial DNA. Cancer Res 56:2033-2038
  23. Jiang S, Cai J, Wallace DC, Jones DP (1999) Cytochrome c-mediated apoptosis in cells lacking mitochondrial DNA. Sig- naling pathway involving release and caspase 3 activation is conserved. J Biol Chem 274:29905-29911
  24. Kim JY, Kim YH, Chang I, Kim S, Pak YK, Oh BH, Yagita H, Jung YK, Oh YJ, Lee MS (2002) Resistance of mitochondrial DNA-deficient cells to TRAIL: role of Bax in TRAIL-induced apoptosis. Oncogene 21:3139-3148
  25. Park SY, Chang I, Kim JY, Kang SW, Park SH, Singh K, Lee MS (2004) Resistance of mitochondrial DNA-depleted cells against cell death: role of mitochondrial superoxide dismutase. J Biol Chem 279:7512-7520
  26. Biswas G, Anandatheerthavarada HK, Avadhani NG (2005) Mechanism of mitochondrial stress-induced resistance to apop- tosis in mitochondrial DNA-depleted C2C12 myocytes. Cell Death Differ 12:266-278
  27. Wolvetang EJ, Johnson KL, Krauer K, Ralph SJ, Linnane AW (1994) Mitochondrial respiratory chain inhibitors induce apop- tosis. FEBS Lett 339:40-44
  28. Peachman KK, Lyles DS, Bass DA (2001) Mitochondria in eosinophils: functional role in apoptosis but not respiration. Proc Natl Acad Sci USA 98:1717-1722
  29. Fitch ME, Chang CM, Parslow TG (2000) The BH3 domain is required for caspase-independent cell death induced by Bax and oligomycin. Cell Death Differ 7:338-349
  30. Matsuyama S, Xu Q, Velours J, Reed JC (1998) The mitochon- drial F0F1-ATPase proton pump is required for function of the proapoptotic protein Bax in yeast and mammalian cells. Mol Cell 1:327-336
  31. Shchepina LA, Pletjushkina OY, Avetisyan AV, Bakeeva LE, Fetisova EK, Izyumov DS, Saprunova VB, Vyssokikh MY, Chernyak BV, Skulachev VP (2002) Oligomycin, inhibitor of the F0 part of H?-ATP-synthase, suppresses the TNF-induced apoptosis. Oncogene 21:8149-8157
  32. Karawajew L, Rhein P, Czerwony G, Ludwig WD (2005) Stress- induced activation of the p53 tumor suppressor in leukemia cells and normal lymphocytes requires mitochondrial activity and reactive oxygen species. Blood 105:4767-4775
  33. Lo ´pez-Rı ´os F, Sa ´nchez-Arago ´M, Garcı ´a-Garcı ´a E, Ortega AD, Berrendero JR, Pozo-Rodrı ´guez F, Lo ´pez-Encuentra A, Ballestı ´n C, Cuezva JM (2007) Loss of the mitochondrial bioenergetic capacity underlies the glucose avidity of carcinomas. Cancer Res 67:9013-9017
  34. Kugler W, Linnemannsto ¨ns K, Veenman L, Gavish M, Lakomek M (2007) Erucylphosphohomocholine-induced cell death in human glioma cells: role of reactive oxygen species. Neural Plast. doi:10.1155/2007/73079 (abstract)
  35. Kugler W, Hu ¨lper P, Lakomek M, Gavish M, Veenman L (2008) Erucylphosphohomocholine-induced apoptosis in human glioma cells: role of the oligomycin-sensitive F0 part of mitochondrial H?-ATP-synthase. Eur J Cancer 6(Suppl):316 (abstract)
  36. Alten J, Veenman L, Gavish M, Lakomek M, Kugler W (2008) Erucylphosphohomocholine-induced cell death and energy metabolism in human malignant glioma cell lines. Abstracts of the 17th Annual Meeting of the Israel Society for Neuroscience (ISFN): 7-9/12/08, Eilat, Israel
  37. Lyamzaev KG, Izyumov DS, Avetisyan AV, Yang F, Pletj- ushkina OY, Chernyak BV (2004) Inhibition of mitochondrial bioenergetics: the effects on structure of mitochondria in the cell and on apoptosis. Acta Biochim Pol 51:553-562
  38. Shoukrun R, Veenman L, Shandalov Y, Leschiner S, Spanier I, Karry R, Katz Y, Weisinger G, Weizman A, Gavish M (2008) The 18-kDa translocator protein, formerly known as the periph- eral-type benzodiazepine receptor, confers proapoptotic and antineoplastic effects in a human colorectal cancer cell line. Pharmacogenet Genomics 18:977-988
  39. Reers M, Smith TW, Chen LB (1991) J-aggregate formation of a carbocyanine as a quantitative fluorescent indicator of membrane potential. Biochemistry 30:4480-4486
  40. Yang NC, Ho WM, Chen YH, Hu ML (2002) A convenient one- step extraction of cellular ATP using boiling water for the luciferin-luciferase assay of ATP. Anal Biochem 306:323-327
  41. Jung JY, Jeong YJ, Jeong TS, Chung HJ, Kim WJ (2008) Inhi- bition of apoptotic signals in overgrowth of human gingival fibroblasts by cyclosporin A treatment. Arch Oral Biol 53:1042- 1049
  42. Appierto V, Tiberio P, Villani MG, Cavadini E, Formelli F (2009) PLAB induction in fenretinide-induced apoptosis of ovarian cancer cells occurs via a ROS-dependent mechanism involving ER stress and JNK activation. Carcinogenesis 30:824- 831
  43. Sa ´nchez Y, Amra ´n D, Ferna ´ndez C, de Blas E, Aller P (2008) Genistein selectively potentiates arsenic trioxide-induced apop- tosis in human leukemia cells via reactive oxygen species gen- eration and activation of reactive oxygen species-inducible protein kinases (p38-MAPK, AMPK). Int J Cancer 123:1205- 1214
  44. Veenman L, Weizman A, Weisinger G, Gavish M (2010) Expression and functions of the 18 kDa Mitochondrial Translo- cator Protein (TSPO) in Health and Disease. Target Drug Deliv Cancer Ther (in press)
  45. Hirsch JD, Beyer CF, Malkowitz L, Beer B, Blume AJ (1989) Mitochondrial benzodiazepine receptors mediate inhibition of mitochondrial respiratory control. Mol Pharmacol 35:157-163
  46. Zisterer DM, Gorman AM, Williams DC, Murphy MP (1992) The effects of the peripheral-type benzodiazepine acceptor ligands, Ro 5-4864 and PK 11195, on mitochondrial respiration. Methods Find Exp Clin Pharmacol 14:85-90
  47. Murphy MP (2009) How mitochondria produce reactive oxygen species. Biochem J 417:1-13
  48. Wallace KB, Starkov AA (2000) Mitochondrial targets of drug toxicity. Annu Rev Pharmacol Toxicol 40:353-388
  49. Oudard S, Boitier E, Miccoli L, Rousset S, Dutrillaux B, Poupon MF (1997) Gliomas are driven by glycolysis: putative roles of hexokinase, oxidative phosphorylation and mitochondrial ultra- structure. Anticancer Res 17:1903-1911
  50. Penefsky HS (1985) Mechanism of inhibition of mitochondrial adenosine triphosphatase by dicyclohexylcarbodiimide and oli- gomycin: relationship to ATP synthesis. Proc Natl Acad Sci USA 82:1589-1593
  51. Arato-Oshima T, Matsui H, Wakizaka A, Homareda H (1996) Mechanism responsible for oligomycin-induced occlusion of Na? within Na/K-ATPase. J Biol Chem 271:25604-25610
  52. Ishii T, Lemas MV, Takeyasu K (1994) Na(?)-, ouabain-, Ca(2?)-, and thapsigargin-sensitive ATPase activity expressed in chimeras between the calcium and the sodium pump alpha sub- units. Proc Natl Acad Sci USA 91:6103-6107
  53. Fedorova OV, Bagrov AY (1997) Inhibition of Na/K ATPase from rat aorta by two Na/K pump inhibitors, ouabain and mari- nobufagenin: evidence of interaction with different alpha-subunit isoforms. Am J Hypertens 10:929-935
  54. Leist M, Single B, Castoldi AF, Ku ¨hnle S, Nicotera P (1997) Intracellular adenosine triphosphate (ATP) concentration: a switch in the decision between apoptosis and necrosis. J Exp Med 185:1481-1486
  55. Zheng J, Ramirez VD (1999) Piceatannol, a stilbene phytochemi- cal, inhibits mitochondrial F0F1-ATPase activity by targeting the F1 complex. Biochem Biophys Res Commun 261:499-503
  56. Kroemer G, Galluzzi L, Brenner C (2007) Mitochondrial mem- brane permeabilization in cell death. Physiol Rev 87:99-163
  57. Gavish M, Bachman I, Shoukrun R, Katz Y, Veenman L, Wei- singer G, Weizman A (1999) Enigma of the peripheral benzo- diazepine receptor. Pharmacol Rev 51:629-650
  58. Davey ME, De Bruijn FJ (2000) A homologue of the tryptophan- rich sensory protein TspO and FixL regulate a novel nutrient deprivation-induced Sinorhizobium meliloti locus. Appl Environ Microbiol 66:5353-5359
  59. Kwong JQ, Henning MS, Starkov AA, Manfredi G (2007) The mitochondrial respiratory chain is a modulator of apoptosis. J Cell Biol 179:1163-1177
  60. Borutaite V, Morkuniene R, Brown CG (2000) Nitric oxide donors, nitrosothiols and mitochondrial respiration inhibitors induce caspase activation by different mechanisms. FEBS Lett 467:155-159
  61. Mills KI, Woodgate LJ, Gilkes AF, Walsh V, Sweeney MC, Brown G, Burnett AK (1999) Inhibition of mitochondrial func- tion in HL60 cells is associated with an increased apoptosis and expression of CD14. Biochem Biophys Res Commun 263:294- 300
  62. Singh S, Khar A (2005) Differential gene expression during apoptosis induced by a serum factor: role of mitochondrial F0-F1 ATP synthase complex. Apoptosis 10:1469-1482
  63. Lueth M, Wronski L, Giese A, Kirschner-Schwabe R, Pietsch T, von Deimling A, Henze G, Kurtz A, Driever PH (2009) Somatic mitochondrial mutations in pilocytic astrocytoma. Cancer Genet Cytogenet 192:30-35
  64. Cleary J, Johnson KM, Opipari AW Jr, Glick GD (2007) Inhi- bition of the mitochondrial F1F0-ATPase by ligands of the peripheral benzodiazepine receptor. Bioorg Med Chem Lett 17:1667-1670
  65. Chen WP, Hung LM, Hsueh CH, Lai LP, Su MJ (2009) Picea- tannol, a derivative of resveratrol, moderately slows I(Na) inac- tivation and exerts antiarrhythmic action in ischaemia-reperfused rat hearts. Br J Pharmacol 157:381-391
  66. Kuo PL, Hsu YL (2008) The grape and wine constituent picea- tannol inhibits proliferation of human bladder cancer cells via blocking cell cycle progression and inducing Fas/membrane bound Fas ligand-mediated apoptotic pathway. Mol Nutr Food Res 52:408-418
  67. Isidoro A, Martı ´nez M, Ferna ´ndez PL, Ortega AD, Santamarı ´a G, Chamorro M, Reed JC, Cuezva JM (2004) Alteration of the bioenergetic phenotype of mitochondria is a hallmark of breast, gastric, lung and oesophageal cancer. Biochem J 378:17-20
  68. Khalil AA (2007) Biomarker discovery: a proteomic approach for brain cancer profiling. Cancer Sci 98:201-213
  69. Dmitrenko V, Shostak K, Boyko O, Khomenko O, Rozumenko V, Malisheva T, Shamayev M, Zozulya Y, Kavsan V (2005) Reduction of the transcription level of the mitochondrial genome in human glioblastoma. Cancer Lett 218:99-107
  70. Krestinina OV, Grachev DE, Odinokova IV, Reiser G, Evtodienko YV, Azarashvili TS (2009) Effect of peripheral benzodiazepine receptor (PBR/TSPO) ligands on opening of Ca2 ? -induced pore and phosphorylation of 3.5-kDa polypep- tide in rat brain mitochondria. Biochemistry (Mosc) 74:421-429
  71. Selivanov VA, Zeak JA, Roca J, Cascante M, Trucco M, Vot- yakova TV (2008) The role of external and matrix pH in mito- chondrial reactive oxygen species generation. J Biol Chem 283:29292-29300
  72. Fusi F, Valoti M, Sgaragli G, Murphy MP (1991) The interaction of antioxidants and structurally related compounds with mito- chondrial oxidative phosphorylation. Methods Find Exp Clin Pharmacol 13:599-603
  73. Novgorodov SA, Gudz TI, Mohr YuE, Goncharenko EN, Yaguzhinsky LS (1989) ATP-synthase complex: the mechanism of control of ion fluxes induced by cumene hydroperoxide in mitochondria. FEBS Lett 247:255-258
  74. Ikemoto H, Tani E, Ozaki I, Kitagawa H, Arita N (2000) Cal- phostin C-mediated translocation and integration of Bax into mitochondria induces cytochrome c release before mitochondrial dysfunction. Cell Death Differ 7:511-520
  75. Tomiyama A, Serizawa S, Tachibana K, Sakurada K, Samejima H, Kuchino Y, Kitanaka C (2006) Critical role for mitochondrial oxidative phosphorylation in the activation of tumor suppressors Bax and Bak. J Natl Cancer Inst 98:1462-1473
  76. De Giorgi F, Lartigue L, Bauer MK, Schubert A, Grimm S, Hanson GT, Remington SJ, Youle RJ, Ichas F (2002) The per- meability transition pore signals apoptosis by directing Bax translocation and multimerization. FASEB J 16:607-609
  77. Handrick R, Ru ¨bel A, Faltin H, Eibl H, Belka C, Jendrossek V (2006) Increased cytotoxicity of ionizing radiation in combina- tion with membrane-targeted apoptosis modulators involves downregulation of protein kinase B/Akt-mediated survival-sig- naling. Radiother Oncol 80:199-206
  78. Le Bras M, Cle ´ment MV, Pervaiz S, Brenner C (2005) Reactive oxygen species and the mitochondrial signaling pathway of cell death. Histol Histopathol 20:205-219
  79. Zorov DB, Juhaszova M, Sollott SJ (2006) Mitochondrial ROS- induced ROS release: an update and review. Biochim Biophys Acta 1757:509-517
  80. Yang J, Wu LJ, Tashino S, Onodera S, Ikejima T (2007) Critical roles of reactive oxygen species in mitochondrial permeability transition in mediating evodiamine-induced human melanoma A375-S2 cell apoptosis. Free Radic Res 41:1099-1108