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BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma

Oncogene volume 35, pages 2052–2061 (2016)Cite this article

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Abstract

Adverse forms of neuroblastoma (NB), a childhood malignancy that develops from immature neuronal progenitor cells frequently carry a gain of chromosome 17q, which leads to overexpression of the antiapoptotic protein BIRC5/Survivin. We have recently shown that high Survivin expression shuts down mitochondrial complex I activity and shifts NB cells from oxidative phosphorylation to aerobic glycolysis, which further increases resistance to cell death induction. This increased glucose consumption sensitized tumor cells to glycolysis inhibitors. Interestingly, in Survivin-overexpressing cells 2-deoxy-d-glucose (2DG) treatment induces re-fusion of mitochondrial networks after 4 h, which coincides with Survivin repression. 2DG selectively acts on Survivin-expressing NB cells and induces autophagic degradation of Survivin via activation of the E3-ubiquitin ligase Parkin, a downstream target of PINK1. Survivin degradation further releases bound Beclin-1, which enhances autophagy and cell death induction. Knockdown of Parkin, however, reduces the sensitivity of Survivin-expressing NB cells to glycolysis inhibition. The selective activity of 2DG treatment on Survivin-overexpressing tumor cells was also confirmed in a xenograft mouse model, which further supports our hypothesis that glycolysis inhibitors might be useful drugs in the treatment of NB.

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References

  1. Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E et al. High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 2000; 19: 617–623.

    Article  CAS  PubMed  Google Scholar 

  2. Verdecia MA, Huang Hk, Dutil E, Kaiser DA, Hunter T, Noel JP . Structure of the human anti-apoptotic protein survivin reveals a dimeric arrangement. Nat Struct Mol Biol 2000; 7: 602–608.

    Article  CAS  Google Scholar 

  3. Morgillo F, Woo JK, Kim ES, Hong WK, Lee HY . Heterodimerization of insulin-like growth factor receptor/epidermal growth factor receptor and induction of survivin expression counteract the antitumor action of erlotinib. Cancer Res 2006; 66: 10100–10111.

    Article  CAS  PubMed  Google Scholar 

  4. Tran J, Master Z, Yu JL, Rak J, Dumont DJ, Kerbel RS . A role for survivin in chemoresistance of endothelial cells mediated by VEGF. Proc Natl Acad Sci 2002; 99: 4349–4354.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Velculescu VE, Madden SL, Zhang L, Lash AE, Yu J, Rago C et al. Analysis of human transcriptomes. Nat Genet 1999; 23: 387–388.

    Article  CAS  PubMed  Google Scholar 

  6. Kang BH, Altieri DC . Regulation of Survivin Stability by the Aryl Hydrocarbon Receptor-interacting Protein. J Biol Chem 2006; 281: 24721–24727.

    Article  CAS  PubMed  Google Scholar 

  7. Dohi T, Beltrami E, Wall NR, Plescia J, Altieri DC . Mitochondrial survivin inhibits apoptosis and promotes tumorigenesis. J Clin Invest 2004; 114: 1117–1127.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Eckelman BPS . Human inhibitor of apoptosis proteins: why XIAP is the black sheep of the family. EMBO Rep 2006; 7: 988–994.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Obexer P, Hagenbuchner J, Unterkircher T, Sachsenmaier N, Seifarth C, Bock G et al. Repression of BIRC5/survivin by FOXO3/FKHRL1 sensitizes human neuroblastoma cells to DNA damage-induced apoptosis. Mol Biol Cell 2009; 20: 2041–2048.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Hagenbuchner J, Kuznetsov AV, Obexer P, Ausserlechner MJ . BIRC5/Survivin enhances aerobic glycolysis and drug resistance by altered regulation of the mitochondrial fusion/fission machinery. Oncogene 2013; 32: 4748–4757.

    Article  CAS  PubMed  Google Scholar 

  11. Zhou W, Yuan J . Necroptosis in health and diseases. Semin Cell Dev Biol 2014; 35: 14–23.

    Article  PubMed  Google Scholar 

  12. Debnath J, Baehrecke EH, Kroemer G . Does autophagy contribute to cell death? Autophagy 2005; 1: 66–74.

    Article  CAS  PubMed  Google Scholar 

  13. Denton D, Xu T, Kumar S . Autophagy as a pro-death pathway. Immunol Cell Biol 2014; 93: 35–42.

    Article  PubMed  Google Scholar 

  14. Shintani T, Klionsky DJ . Autophagy in health and disease: a double-edged sword. Science 2004; 306: 990–995.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Kang R, Zeh HJ, Lotze MT, Tang D . The Beclin 1 network regulates autophagy and apoptosis. Cell Death Differ 2011; 18: 571–580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Pattingre S, Tassa A, Qu X, Garuti R, Liang XH, Mizushima N et al. Bcl-2 antiapoptotic proteins inhibit beclin 1-dependent autophagy. Cell 2005; 122: 927–939.

    Article  CAS  PubMed  Google Scholar 

  17. Niu TK, Cheng Y, Ren X, Yang JM . Interaction of Beclin 1 with survivin regulates sensitivity of human glioma cells to TRAIL-induced apoptosis. FEBS Lett 2010; 584: 3519–3524.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Abe A, Kokuba H . Harmol induces autophagy and subsequent apoptosis in U251MG human glioma cells through the downregulation of survivin. Oncol Rep 2012; 29: 1333–1342.

    Article  Google Scholar 

  19. Ganapathy-Kanniappan S, Geschwind JF . Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 2013; 12: 152.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Stern R, Shuster S, Neudecker BA, Formby B . Lactate stimulates fibroblast expression of hyaluronan and CD44: the Warburg effect revisited. Exp Cell Res 2002; 276: 24–31.

    Article  CAS  PubMed  Google Scholar 

  21. Wang X, Perez E, Liu R, Yan LJ, Mallet RT, Yang SH . Pyruvate protects mitochondria from oxidative stress in human neuroblastoma SK-N-SH cells. Brain Res 2007; 1132: 1–9.

    Article  CAS  PubMed  Google Scholar 

  22. De Lena M, Lorusso V, Latorre A, Fanizza G, Gargano G, Caporusso L et al. Paclitaxel, cisplatin and lonidamine in advanced ovarian cancer. A phase II study. Eur J Cancer 2001; 37: 364–368.

    Article  CAS  PubMed  Google Scholar 

  23. Maher J, Krishan A, Lampidis T . Greater cell cycle inhibition and cytotoxicity induced by 2-deoxy-d-glucose in tumor cells treated under hypoxic vs aerobic conditions. Cancer Chemother Pharmacol 2004; 53: 116–122.

    Article  CAS  PubMed  Google Scholar 

  24. Stein M, Lin H, Jeyamohan C, Dvorzhinski D, Gounder M, Bray K et al. Targeting tumor metabolism with 2-deoxyglucose in patients with castrate-resistant prostate cancer and advanced malignancies. Prostate 2010; 70: 1388–1394.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Sachita K, Yu HJ, Yun JW, Lee JS, Cho SD . YM155 induces apoptosis through downregulation of specificity protein 1 and myeloid cell leukemia-1 in human oral cancer cell lines. J Oral Pathol Med 2014, e-pub ahead of print 5 December 2014 doi:10.1111/jop.12299.

    Article  Google Scholar 

  26. Cheng Y, Diao DM, Zhang H, Zhang HF, Song YC, Dang C-X et al. Proliferation enhanced by NGF-NTRK1 signaling makes pancreatic cancer cells more sensitive to 2DG-induced apoptosis. Int J Med Sci 2013; 10: 634–640.

    Article  PubMed  PubMed Central  Google Scholar 

  27. Ramírez-Peinado S, Alcázar-Limones F, Lagares-Tena L, El Mjiyad N, Caro-Maldonado A, Tirado OM et al. 2-Deoxyglucose induces noxa-dependent apoptosis in alveolar rhabdomyosarcoma. Cancer Res 2011; 71: 6796–6806.

    Article  PubMed  Google Scholar 

  28. Ramírez-Peinado S, León-Annicchiarico CL, Galindo-Moreno J, Iurlaro R, Caro-Maldonado A, Prehn JH et al. Glucose-starved cells do not engage in prosurvival autophagy. J Biol Chem 2013; 288: 30387–30398.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Huang CY, Kuo WT, Huang YC, Lee TC, Yu LCH . Resistance to hypoxia-induced necroptosis is conferred by glycolytic pyruvate scavenging of mitochondrial superoxide in colorectal cancer cells. Cell Death Dis 2013; 4: e622.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Singh R, Cuervo A . Autophagy in the cellular energetic balance. Cell Metab 2011; 13: 495–504.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Sheen JH, Zoncu R, Kim D, Sabatini D . Defective regulation of autophagy upon leucine deprivation reveals a targetable liability of human melanoma cells in vitro and in vivo. Cancer Cell 2011; 19: 613–628.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Stock C, Bozsaky E, Watzinger F, Poetschger U, Orel L, Lion T et al. Genes proximal and distal to MYCN are highly expressed in human neuroblastoma as visualized by comparative expressed sequence hybridization. Am J Pathol 2008; 172: 203–214.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Saita S, Shirane M, Nakayama KI . Selective escape of proteins from the mitochondria during mitophagy. Nat Commun 2013; 4: 1410.

    Article  PubMed  Google Scholar 

  34. Novak I . Mitophagy: a complex mechanism of mitochondrial removal. Antioxid Redox Signal 2012; 17: 794–802.

    Article  CAS  PubMed  Google Scholar 

  35. Sandebring A, Thomas KJ, Beilina A, Beilina AF, van der Brug M, Cleland MM et al. Mitochondrial alterations in PINK1 deficient cells are influenced by calcineurin-dependent dephosphorylation of dynamin-related protein 1. PLos One 2009; 4: e5701.

    Article  PubMed  PubMed Central  Google Scholar 

  36. Yamamoto A, Friedlein A, Imai Y, Takahashi R, Kahle PJ, Haass C . Parkin phosphorylation and modulation of its E3 ubiquitin ligase activity. J Biol Chem 2005; 280: 3390–3399.

    Article  CAS  PubMed  Google Scholar 

  37. Shutt D, O'Dorisio MS, Aykin-Burns N, Spitz D . 2-Deoxy-D-glucose induces oxidative stress and cell killing in human neuroblastoma cells. Cancer Biol Ther 2010; 9: 853–861.

    Article  CAS  PubMed  Google Scholar 

  38. Groner B, Weiss A . Targeting survivin in cancer: novel drug development approaches. BioDrugs 2014; 28: 27–39.

    Article  CAS  PubMed  Google Scholar 

  39. Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L et al. Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 2011; 118: 2191–2199.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Paik S, Shak S, Tang G, Kim C, Baker J, Cronin M et al. A multigene assay to predict recurrence of tamoxifen-treated, node-negative breast cancer. N Engl J Med 2004; 351: 2817–2826.

    Article  CAS  PubMed  Google Scholar 

  41. Zhang C, Lin M, Wu R, Wang X, Yang B, Levine AJ et al. Parkin, a p53 target gene, mediates the role of p53 in glucose metabolism and the Warburg effect. Proc Natl Acad Sci 2011; 108: 16259–16264.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Hoepken HH, Gispert S, Morales B, Wingerter O, Del Turco D, Mülsch A et al. Mitochondrial dysfunction, peroxidation damage and changes in glutathione metabolism in PARK6. Neurobiol Dis 2007; 25: 401–411.

    Article  CAS  PubMed  Google Scholar 

  43. Michiorri S, Gelmetti V, Giarda E, Lombardi F, Romano F, Marongiu R et al. The Parkinson-associated protein PINK1 interacts with Beclin1 and promotes autophagy. Cell Death Differ 2010; 17: 962–974.

    Article  CAS  PubMed  Google Scholar 

  44. Altieri DC . Survivin, versatile modulation of cell division and apoptosis in cancer. Oncogene 2003; 22: 8581–8589.

    Article  CAS  PubMed  Google Scholar 

  45. Caldas H, Holloway MP, Hall BM, Qualman SJ, Altura RA . Survivin-directed RNA interference cocktail is a potent suppressor of tumour growth in vivo. J Med Genet 2006; 43: 119–128.

    Article  CAS  PubMed  Google Scholar 

  46. Uchida H, Tanaka T, Sasaki K, Kato K, Dehari H, Ito Y et al. Adenovirus-mediated transfer of sirna against survivin induced apoptosis and attenuated tumor cell growth in vitro and in vivo. Mol Ther 2004; 10: 162–171.

    Article  CAS  PubMed  Google Scholar 

  47. Nakahara T, Takeuchi M, Kinoyama I, Minematsu T, Shirasuna K, Matsuhisa A et al. YM155, a novel small-molecule survivin suppressant, induces regression of established human hormone-refractory prostate tumor xenografts. Cancer Res 2007; 67: 8014–8021.

    Article  CAS  PubMed  Google Scholar 

  48. Chang CC, Heller JD, Kuo J, Huang RC . Tetra-O-methyl nordihydroguaiaretic acid induces growth arrest and cellular apoptosis by inhibiting Cdc2 and survivin expression. Proc Natl Acad Sci USA 2004; 101: 13239–13244.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Rödel F, Frey B, Leitmann W, Capalbo G, Weiss C, Rödel C . Survivin antisense oligonucleotides effectively radiosensitize colorectal cancer cells in both tissue culture and murine xenograft models. Int J Radiat Oncol Biol Phys 2008; 71: 247–255.

    Article  PubMed  Google Scholar 

  50. Wobser M, Keikavoussi P, Kunzmann V, Weininger M, Andersen M, Becker J . Complete remission of liver metastasis of pancreatic cancer under vaccination with a HLA-A2 restricted peptide derived from the universal tumor antigen survivin. Cancer Immunol Immunother 2006; 55: 1294–1298.

    Article  CAS  PubMed  Google Scholar 

  51. Tolcher AW, Quinn DI, Ferrari A, Ahmann F, Giaccone G, Drake T et al. A phase II study of YM155, a novel small-molecule suppressor of survivin, in castration-resistant taxane-pretreated prostate cancer. Ann Oncol 2012; 23: 968–973.

    Article  CAS  PubMed  Google Scholar 

  52. Satoh T, Okamoto I, Miyazaki M, Morinaga R, Tsuya A, Hasegawa Y et al. Phase I study of YM155, a novel survivin suppressant, in patients with advanced solid tumors. Clin Cancer Res 2009; 15: 3872–3880.

    Article  CAS  PubMed  Google Scholar 

  53. Gurbuxani S, Xu Y, Keerthivasan G, Wickrema A, Crispino JD . Differential requirements for survivin in hematopoietic cell development. Proc Natl Acad Sci USA 2005; 102: 11480–11485.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Xing Z, Conway EM, Kang C, Winoto A . Essential role of survivin, an inhibitor of apoptosis protein, in T cell development, maturation, and homeostasis. J Exp Med 2004; 199: 69–80.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Mesri M, Morales-Ruiz M, Ackermann EJ, Bennett CF, Pober JS, Sessa WC et al. Suppression of vascular endothelial growth factor-mediated endothelial cell protection by survivin targeting. Am J Pathol 2001; 158: 1757–1765.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Blanc-Brude OP, Mesri M, Wall NR, Plescia J, Dohi T, Altieri DC . Therapeutic targeting of the survivin pathway in cancer: initiation of mitochondrial apoptosis and suppression of tumor-associated angiogenesis. Clin Cancer Res 2003; 9: 2683–2692.

    CAS  PubMed  Google Scholar 

  57. Fortugno P, Beltrami E, Plescia J, Fontana J, Pradhan D, Marchisio PC et al. Regulation of survivin function by Hsp90. Proc Natl Acad Sci 2003; 100: 13791–13796.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Plescia J, Salz W, Xia F, Pennati M, Zaffaroni N, Daidone MG et al. Rational design of shepherdin, a novel anticancer agent. Cancer Cell 2005; 7: 457–468.

    Article  CAS  PubMed  Google Scholar 

  59. Fukuda SF . The antiapoptosis protein survivin is associated with cell cycle entry of normal cord blood CD34+ cells and modulates cell cycle and proliferation of mouse hematopoietic progenitor cells. Blood 2002; 100: 2463–2471.

    Article  CAS  PubMed  Google Scholar 

  60. Bean JF, Qiu YY, Yu S, Clark S, Chu F, Madonna MB . Glycolysis inhibition and its effect in doxorubicin resistance in neuroblastoma. J Pediatr Surg 2014; 49: 981–984.

    Article  PubMed  Google Scholar 

  61. Chuang JH, Chou MH, Tai MH, Lin TK, Liou CW, Chen T et al. 2-Deoxyglucose treatment complements the cisplatin- or BH3-only mimetic-induced suppression of neuroblastoma cell growth. Int J Biochem Cell Biol 2013; 45: 944–951.

    Article  CAS  PubMed  Google Scholar 

  62. Grignani F, Kinsella T, Mencarelli A, Valtieri M, Riganelli D, Grignani F et al. High-efficiency gene transfer and selection of human hematopoietic progenitor cells with a hybrid EBV/retroviral vector expressing the green fluorescence protein. Cancer Res 1998; 58: 14–19.

    CAS  PubMed  Google Scholar 

  63. Ausserlechner MJ, Obexer P, Deutschmann A, Geiger K, Kofler R . A retroviral expression system based on tetracycline-regulated tricistronic transactivator/repressor vectors for functional analyses of anti-proliferative and toxic genes. Mol Cancer Ther 2006; 5: 1927–1934.

    Article  CAS  PubMed  Google Scholar 

  64. Hagenbuchner J, Kuznetsov A, Hermann M, Hausott B, Obexer P, Ausserlechner MJ . FOXO3-induced reactive oxygen species are regulated by BCL2L11 (Bim) and SESN3. J Cell Sci 2012; 125: 1191–1203.

    Article  CAS  PubMed  Google Scholar 

  65. Geiger K, Hagenbuchner J, Rupp M, Fiegl H, Sergi C, Meister B et al. FOXO3/FKHRL1 is activated by 5-aza-2-deoxycytidine and induces silenced caspase-8 in neuroblastoma. Mol Biol Cell 2012; 23: 2226–2234.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hagenbuchner J, Ausserlechner MJ, Porto V, David R, Meister B, Bodner M et al. The anti-apoptotic protein BCL2L1/Bcl-xL is neutralized by pro-apoptotic PMAIP1/Noxa in neuroblastoma, thereby determining bortezomib sensitivity independent of prosurvival MCL1 expression. J Biol Chem 2010; 285: 6904–6912.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hagenbuchner J, Kiechl-Kohlendorfer U, Obexer P, Ausserlechner MJ . A novel Mcl1 variant inhibits apoptosis via increased Bim sequestration. Oncotarget 2013; 4: 1241–1252.

    Article  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We thank Dr Hermann Dietrich and his team for the animal care. This work was supported by the intramural funding program of the Medical University Innsbruck for young scientists MUI-START (P2012032014) and by grants from the ‘Provita Kinderleukämie Stiftung’, the ‘Medizinische Forschungsfond Tirol’ and ‘SVP-Frauen-Initiative’. This study is supported by the ‘Tiroler Landeskrankenanstalten Ges.m.b.H. (TILAK)’ and the ‘Tyrolean Cancer Society’.

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  1. Department of Pediatrics II, Medical University Innsbruck, Innsbruck, Austria

    J Hagenbuchner, U Kiechl-Kohlendorfer & P Obexer

  2. Tyrolean Cancer Research Institute, Innsbruck, Austria

    P Obexer

  3. Department of Pediatrics I, Medical University Innsbruck, Innsbruck, Austria

    M J Ausserlechner

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Hagenbuchner, J., Kiechl-Kohlendorfer, U., Obexer, P. et al. BIRC5/Survivin as a target for glycolysis inhibition in high-stage neuroblastoma. Oncogene 35, 2052–2061 (2016). https://doi.org/10.1038/onc.2015.264

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