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How to train glioma cells to die: molecular challenges in cell death

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Abstract

The five-year survival rate for patients with malignant glioma is less than 10 %. Despite aggressive chemo/radiotherapy these tumors have remained resistant to almost every interventional strategy evaluated in patients. Resistance to these agents is attributed to extrinsic mechanisms such as the tumor microenvironment, poor drug penetration, and tumoral heterogeneity. In addition, genetic and molecular examination of these tumors has revealed defective apoptotic regulation, enhanced pro-survival autophagy signaling, and a propensity for necrosis that aids in the adaptation to environmental stress and resistance to treatment. The combination of extrinsic and intrinsic hallmarks in glioma contributes to the multifaceted resistance to traditional anti-tumor agents. Here we describe the biology of the disease relevant to therapeutic resistance, with a specific focus on molecular deregulation of cell death pathways. Emerging studies investigating the targeting of these pathways including BH3 mimetics and autophagy inhibitors that are being evaluated in both the preclinical and clinical settings are discussed. This review highlights the pathways exploited by glioblastoma cells that drive their hallmark pro-survival predisposition and makes therapy development such a challenge.

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References

  1. Louis DN, Ohgaki H, Wiestler OD, Cavenee WK, Burger PC, Jouvet A et al (2007) The 2007 WHO classification of tumours of the central nervous system. Acta Neuropathol 114(2):97–109

    Article  PubMed  PubMed Central  Google Scholar 

  2. Jiang YG, Peng Y, Koussougbo KS (2011) Necroptosis: a novel therapeutic target for glioblastoma. Med Hypotheses 76(3):350–352

    Article  PubMed  Google Scholar 

  3. Tait SW, Green DR (2010) Mitochondria and cell death: outer membrane permeabilization and beyond. Nat Rev Mol Cell Biol 11(9):621–632

    Article  PubMed  CAS  Google Scholar 

  4. Chipuk JE, Moldoveanu T, Llambi F, Parsons MJ, Green DR (2010) The BCL-2 family reunion. Mol Cell 37(3):299–310

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  5. Cartron PF, Loussouarn D, Campone M, Martin SA, Vallette FM (2012) Prognostic impact of the expression/phosphorylation of the BH3-only proteins of the BCL-2 family in glioblastoma multiforme. Cell Death Dis 3:e421

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  6. Strik H, Deininger M, Streffer J, Grote E, Wickboldt J, Dichgans J et al (1999) BCL-2 family protein expression in initial and recurrent glioblastomas: modulation by radio-chemotherapy. J Neurol Neurosurg Psychiatry 67(6):763–768

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  7. Qiu B, Wang Y, Tao J, Wang Y (2012) Expression and correlation of Bcl-2 with pathological grades in human glioma stem cells. Oncol Rep 28(1):155–160

    PubMed  Google Scholar 

  8. Nagane M, Levitzki A, Gazit A, Cavenee WK, Huang HJ (1998) Drug resistance of human glioblastoma cells conferred by a tumor-specific mutant epidermal growth factor receptor through modulation of Bcl-XL and caspase-3-like proteases. Proc Natl Acad Sci USA 95(10):5724–5729

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  9. Zhu H, Cao X, Ali-Osman F, Keir S, Lo HW (2010) EGFR and EGFRvIII interact with PUMA to inhibit mitochondrial trans-localization of PUMA and PUMA-mediated apoptosis independent of EGFR kinase activity. Cancer Lett 294(1):101–110

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  10. Stegh AH, Kim H, Bachoo RM, Forloney KL, Zhang J, Schulze H et al (2007) Bcl2L12 inhibits post-mitochondrial apoptosis signaling in glioblastoma. Genes Dev 21(1):98–111

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  11. Stegh AH, Kesari S, Mahoney JE, Jenq HT, Forloney KL, Protopopov A et al (2008) Bcl2L12-mediated inhibition of effector caspase-3 and caspase-7 via distinct mechanisms in glioblastoma. Proc Natl Acad Sci USA 105(31):10703–10708

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  12. Stegh AH, Brennan C, Mahoney JA, Forloney KL, Jenq HT, Luciano JP et al (2010) Glioma oncoprotein Bcl2L12 inhibits the p53 tumor suppressor. Genes Dev 24(19):2194–2204

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  13. Tagscherer KE, Fassl A, Campos B, Farhadi M, Kraemer A, Bock BC et al (2008) Apoptosis-based treatment of glioblastomas with ABT-737, a novel small molecule inhibitor of Bcl-2 family proteins. Oncogene 27(52):6646–6656

    Article  PubMed  CAS  Google Scholar 

  14. Manero F, Gautier F, Gallenne T, Cauquil N, Gree D, Cartron PF et al (2006) The small organic compound HA14-1 prevents Bcl-2 interaction with Bax to sensitize malignant glioma cells to induction of cell death. Cancer Res 66(5):2757–2764

    Article  PubMed  CAS  Google Scholar 

  15. Dodou K, Anderson RJ, Small DA, Groundwater PW (2005) Investigations on gossypol: past and present developments. Expert Opin Investig Drugs 14(11):1419–1434

    Article  PubMed  CAS  Google Scholar 

  16. Wagenknecht B, Glaser T, Naumann U, Kugler S, Isenmann S, Bahr M et al (1999) Expression and biological activity of X-linked inhibitor of apoptosis (XIAP) in human malignant glioma. Cell Death Differ 6(4):370–376

    Article  PubMed  CAS  Google Scholar 

  17. Chakravarti A, Noll E, Black PM, Finkelstein DF, Finkelstein DM, Dyson NJ et al (2002) Quantitatively determined survivin expression levels are of prognostic value in human gliomas. J Clin Oncol 20(4):1063–1068

    Article  PubMed  CAS  Google Scholar 

  18. Ziegler DS, Wright RD, Kesari S, Lemieux ME, Tran MA, Jain M et al (2008) Resistance of human glioblastoma multiforme cells to growth factor inhibitors is overcome by blockade of inhibitor of apoptosis proteins. J Clin Investig 118(9):3109–3122

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  19. Chakravarti A, Zhai GG, Zhang M, Malhotra R, Latham DE, Delaney MA et al (2004) Survivin enhances radiation resistance in primary human glioblastoma cells via caspase-independent mechanisms. Oncogene 23(45):7494–7506

    Article  PubMed  CAS  Google Scholar 

  20. Fulda S, Wick W, Weller M, Debatin KM (2002) Smac agonists sensitize for Apo2L/TRAIL- or anticancer drug-induced apoptosis and induce regression of malignant glioma in vivo. Nat Med 8(8):808–815

    PubMed  CAS  Google Scholar 

  21. Wagner L, Marschall V, Karl S, Cristofanon S, Zobel K, Deshayes K et al (2013) Smac mimetic sensitizes glioblastoma cells to Temozolomide-induced apoptosis in a RIP1- and NF-kappaB-dependent manner. Oncogene 32(8):988–997

    Article  PubMed  CAS  Google Scholar 

  22. Begg AC, Stewart FA, Vens C (2011) Strategies to improve radiotherapy with targeted drugs. Nat Rev Cancer 11(4):239–253

    Article  PubMed  CAS  Google Scholar 

  23. Venur VA, Peereboom DM, Ahluwalia MS (2015) Current medical treatment of glioblastoma. Cancer Treat Res 163:103–115

    Article  PubMed  Google Scholar 

  24. Stupp R, Mason WP, van den Bent MJ, Weller M, Fisher B, Taphoorn MJ et al (2005) Radiotherapy plus concomitant and adjuvant temozolomide for glioblastoma. N Engl J Med 352(10):987–996

    Article  PubMed  CAS  Google Scholar 

  25. Kondo N, Takahashi A, Ono K, Ohnishi T (2010) DNA damage induced by alkylating agents and repair pathways. J Nucleic Acids 2010:543531

    Article  PubMed  PubMed Central  Google Scholar 

  26. Weller M, Stupp R, Reifenberger G, Brandes AA, van den Bent MJ, Wick W et al (2010) MGMT promoter methylation in malignant gliomas: ready for personalized medicine? Nat Rev Neurol 6(1):39–51

    Article  PubMed  CAS  Google Scholar 

  27. Barazzuol L, Jena R, Burnet NG, Meira LB, Jeynes JC, Kirkby KJ et al (2013) Evaluation of poly (ADP-ribose) polymerase inhibitor ABT-888 combined with radiotherapy and temozolomide in glioblastoma. Radiat Oncol 8:65

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  28. Lin F, de Gooijer MC, Roig EM, Buil LC, Christner SM, Beumer JH et al (2014) ABCB1, ABCG2, and PTEN determine the response of glioblastoma to temozolomide and ABT-888 therapy. Clin Cancer Res Off J Am Assoc Cancer Res 20(10):2703–2713

    Article  CAS  Google Scholar 

  29. Tentori L, Leonetti C, Scarsella M, D’Amati G, Vergati M, Portarena I et al (2003) Systemic administration of GPI 15427, a novel poly(ADP-ribose) polymerase-1 inhibitor, increases the antitumor activity of temozolomide against intracranial melanoma, glioma, lymphoma. Clin Cancer Res Off J Am Assoc Cancer Res 9(14):5370–5379

    CAS  Google Scholar 

  30. Donawho CK, Luo Y, Luo Y, Penning TD, Bauch JL, Bouska JJ et al (2007) ABT-888, an orally active poly(ADP-ribose) polymerase inhibitor that potentiates DNA-damaging agents in preclinical tumor models. Clin Cancer Res Off J Am Assoc Cancer Res 13(9):2728–2737

    Article  CAS  Google Scholar 

  31. Levine B, Kroemer G (2008) Autophagy in the pathogenesis of disease. Cell 132(1):27–42

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  32. Liu EY, Ryan KM (2012) Autophagy and cancer–issues we need to digest. J Cell Sci 125(Pt 10):2349–2358

    Article  PubMed  Google Scholar 

  33. White E, DiPaola RS (2009) The double-edged sword of autophagy modulation in cancer. Clin Cancer Res 15(17):5308–5316

    Article  PubMed  PubMed Central  Google Scholar 

  34. Fan QW, Cheng C, Hackett C, Feldman M, Houseman BT, Nicolaides T et al (2010) Akt and autophagy cooperate to promote survival of drug-resistant glioma. Sci Signal 3(147):ra81

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  35. Shen J, Zheng H, Ruan J, Fang W, Li A, Tian G et al (2013) Autophagy inhibition induces enhanced proapoptotic effects of ZD6474 in glioblastoma. Br J Cancer 109(1):164–171

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  36. Gammoh N, Lam D, Puente C, Ganley I, Marks PA, Jiang X (2012) Role of autophagy in histone deacetylase inhibitor-induced apoptotic and nonapoptotic cell death. Proc Natl Acad Sci USA 109(17):6561–6565

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  37. Li Y, Zhu H, Zeng X, Fan J, Qian X, Wang S et al (2013) Suppression of autophagy enhanced growth inhibition and apoptosis of interferon-beta in human glioma cells. Mol Neurobiol 47(3):1000–1010

    Article  PubMed  CAS  Google Scholar 

  38. Ge PF, Zhang JZ, Wang XF, Meng FK, Li WC, Luan YX et al (2009) Inhibition of autophagy induced by proteasome inhibition increases cell death in human SHG-44 glioma cells. Acta Pharmacol Sin 30(7):1046–1052

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  39. Chen Y, Meng D, Wang H, Sun R, Wang D, Wang S, et al (2014) VAMP8 facilitates cellular proliferation and temozolomide resistance in human glioma cells. Neuro Oncol 17(3):407–418

  40. Cho HY, Wang W, Jhaveri N, Lee DJ, Sharma N, Dubeau L et al (2014) NEO212, temozolomide conjugated to perillyl alcohol, is a novel drug for effective treatment of a broad range of temozolomide-resistant gliomas. Mol Cancer Ther 13(8):2004–2017

    Article  PubMed  CAS  Google Scholar 

  41. Curry RC, Dahiya S, Alva Venur V, Raizer JJ, Ahluwalia MS (2015) Bevacizumab in high-grade gliomas: past, present, and future. Expert Rev Anticancer Ther 15(4):387–397

    Article  PubMed  CAS  Google Scholar 

  42. Gilbert MR, Sulman EP, Mehta MP (2014) Bevacizumab for newly diagnosed glioblastoma. New Engl J Med 370(21):2048–2049

    Article  PubMed  CAS  Google Scholar 

  43. Chinot OL, Wick W, Cloughesy T (2014) Bevacizumab for newly diagnosed glioblastoma. New Engl J Med 370(21):2049

    Article  PubMed  Google Scholar 

  44. Hu YL, DeLay M, Jahangiri A, Molinaro AM, Rose SD, Carbonell WS et al (2012) Hypoxia-induced autophagy promotes tumor cell survival and adaptation to antiangiogenic treatment in glioblastoma. Cancer Res 72(7):1773–1783

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  45. Golden EB, Cho HY, Jahanian A, Hofman FM, Louie SG, Schonthal AH et al (2014) Chloroquine enhances temozolomide cytotoxicity in malignant gliomas by blocking autophagy. Neurosurg Focus 37(6):E12

    Article  PubMed  Google Scholar 

  46. Rosenfeld MR, Ye X, Supko JG, Desideri S, Grossman SA, Brem S et al (2014) A phase I/II trial of hydroxychloroquine in conjunction with radiation therapy and concurrent and adjuvant temozolomide in patients with newly diagnosed glioblastoma multiforme. Autophagy 10(8):1359–1368

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  47. Alonso MM, Jiang H, Yokoyama T, Xu J, Bekele NB, Lang FF et al (2008) Delta-24-RGD in combination with RAD001 induces enhanced anti-glioma effect via autophagic cell death. Mol Ther 16(3):487–493

    Article  PubMed  CAS  Google Scholar 

  48. Zong WX, Thompson CB (2006) Necrotic death as a cell fate. Genes Dev 20(1):1–15

    Article  PubMed  CAS  Google Scholar 

  49. Stegh AH, Chin L, Louis DN, DePinho RA (2008) What drives intense apoptosis resistance and propensity for necrosis in glioblastoma? A role for Bcl2L12 as a multifunctional cell death regulator. Cell Cycle 7(18):2833–2839

    Article  PubMed  CAS  Google Scholar 

  50. Flannery T, McQuaid S, McGoohan C, McConnell RS, McGregor G, Mirakhur M et al (2006) Cathepsin S expression: an independent prognostic factor in glioblastoma tumours—a pilot study. Int J Cancer J Int Du cancer 119(4):854–860

    Article  CAS  Google Scholar 

  51. Keerthivasan S, Keerthivasan G, Mittal S, Chauhan SS (2007) Transcriptional upregulation of human cathepsin L by VEGF in glioblastoma cells. Gene 399(2):129–136

    Article  PubMed  CAS  Google Scholar 

  52. Ouyang L, Shi Z, Zhao S, Wang FT, Zhou TT, Liu B et al (2012) Programmed cell death pathways in cancer: a review of apoptosis, autophagy and programmed necrosis. Cell Prolif 45(6):487–498

    Article  PubMed  CAS  Google Scholar 

  53. Melo-Lima S, Celeste Lopes M, Mollinedo F (2014) Necroptosis is associated with low procaspase-8 and active RIPK1 and -3 in human glioma cells. Oncoscience 1(10):649–664

    Article  PubMed  PubMed Central  Google Scholar 

  54. Kang TB, Yang SH, Toth B, Kovalenko A, Wallach D (2014) Activation of the NLRP3 inflammasome by proteins that signal for necroptosis. Methods Enzymol 545:67–81

    Article  PubMed  CAS  Google Scholar 

  55. Reardon DA, Wucherpfennig KW, Freeman G, Wu CJ, Chiocca EA, Wen PY et al (2013) An update on vaccine therapy and other immunotherapeutic approaches for glioblastoma. Expert Rev Vaccines 12(6):597–615

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  56. Stupp R, Wong ET, Kanner AA, Steinberg D, Engelhard H, Heidecke V et al (2012) NovoTTF-100A versus physician’s choice chemotherapy in recurrent glioblastoma: a randomised phase III trial of a novel treatment modality. Eur J Cancer 48(14):2192–2202

    Article  PubMed  Google Scholar 

  57. Turk B, Turk V (2009) Lysosomes as “suicide bags” in cell death: myth or reality? J Biol Chem 284(33):21783–21787

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  58. Blomgran R, Zheng L, Stendahl O (2007) Cathepsin-cleaved Bid promotes apoptosis in human neutrophils via oxidative stress-induced lysosomal membrane permeabilization. J Leukoc Biol 81(5):1213–1223

    Article  PubMed  CAS  Google Scholar 

  59. Racoma IO, Meisen WH, Wang QE, Kaur B, Wani AA (2013) Thymoquinone inhibits autophagy and induces cathepsin-mediated, caspase-independent cell death in glioblastoma cells. PLoS One 8(9):e72882

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  60. Boya P, Kroemer G (2008) Lysosomal membrane permeabilization in cell death. Oncogene 27(50):6434–6451

    Article  PubMed  CAS  Google Scholar 

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Acknowledgments

The authors acknowledge Servier Medical Art Image Bank (http://www.servier.com/Powerpoint-image-bank) for the free image components used to create Figs. 1, 2, and 3 (http://creativecommons.org/licenses/by/3.0/legalcode).

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Authors and Affiliations

  1. Department of Neurological Surgery, The Ohio State University Medical Center, 385-B OSUCCC, 410 West 12th Avenue, Columbus, OH, 43210, USA

    Jeffrey Wojton, Walter Hans Meisen & Balveen Kaur

  2. Department of Pharmacology and Cancer Biology, Duke University, Durham, NC, 27710, USA

    Jeffrey Wojton

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  1. Jeffrey Wojton
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Correspondence to Balveen Kaur.

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Wojton, J., Meisen, W.H. & Kaur, B. How to train glioma cells to die: molecular challenges in cell death. J Neurooncol 126, 377–384 (2016). https://doi.org/10.1007/s11060-015-1980-1

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  • DOI: https://doi.org/10.1007/s11060-015-1980-1

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