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Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival

Oncogene volume 34, pages 3305–3314 (2015)Cite this article

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Abstract

Glioblastomas (GBMs) are resistant to current therapy protocols and identification of molecules that target these tumors is crucial. Interaction of secreted heat-shock protein 70 (Hsp70)–Hsp90-organizing protein (HOP) with cellular prion protein (PrPC) triggers a large number of trophic effects in the nervous system. We found that both PrPC and HOP are highly expressed in human GBM samples relative to non-tumoral tissue or astrocytoma grades I–III. High levels of PrPC and HOP were associated with greater GBM proliferation and lower patient survival. HOP–PrPC binding increased GBM proliferation in vitro via phosphatidylinositide 3-kinase and extracellular-signal-regulated kinase pathways, and a HOP peptide mimicking the PrPC binding site (HOP230–245) abrogates this effect. PrPC knockdown impaired tumor growth and increased survival of mice with tumors. In mice, intratumor delivery of HOP230–245 peptide impaired proliferation and promoted apoptosis of GBM cells. In addition, treatment with HOP230–245 peptide inhibited tumor growth, maintained cognitive performance and improved survival. Thus, together, the present results indicate that interfering with PrPC–HOP engagement is a promising approach for GBM therapy.

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References

  1. Furnari FB, Fenton T, Bachoo RM, Mukasa A, Stommel JM, Stegh A et al. Malignant astrocytic glioma: genetics, biology, and paths to treatment. Genes Dev 2007; 21: 2683–2710.

    Article  CAS  PubMed  Google Scholar 

  2. Ohgaki H, Kleihues P . The definition of primary and secondary glioblastoma. Clin Cancer Res 2013; 19: 764–772.

    Article  CAS  PubMed  Google Scholar 

  3. Westphal M, Lamszus K . The neurobiology of gliomas: from cell biology to the development of therapeutic approaches. Nat Rev Neurosci 2011; 12: 495–508.

    Article  CAS  PubMed  Google Scholar 

  4. Jones TS, Holland EC . Standard of care therapy for malignant glioma and its effect on tumor and stromal cells. Oncogene 2012; 31: 1995–2006.

    Article  CAS  PubMed  Google Scholar 

  5. Linden R, Martins VR, Prado MAM, Cammarota M, Izquierdo I, Brentani RR . Physiology of the prion protein. Physiol Rev 2008; 88: 673–728.

    Article  CAS  PubMed  Google Scholar 

  6. Martins VR, Beraldo FH, Hajj GN, Lopes MH, Lee KS, Prado MAM et al. Prion protein: orchestrating neurotrophic activities. Curr Issues Mol Biol 2010; 12: 63–86.

    CAS  PubMed  Google Scholar 

  7. Erlich RB, Kahn SA, Lima FRS, Muras AG, Martins RAP, Linden R, et al. STI1 promotes glioma proliferation through MAPK and PI3K pathways. Glia 2007; 55: 1690–1698.

    Article  PubMed  Google Scholar 

  8. Maciejewski A, Prado MA, Choy W-Y . (1)H, (15)N and (13)C backbone resonance assignments of the TPR1 and TPR2A domains of mouse STI1. Biomol NMR Assign 2013; 7: 305–310.

    Article  CAS  PubMed  Google Scholar 

  9. Lee C-T, Graf C, Mayer FJ, Richter SM, Mayer MP . Dynamics of the regulation of Hsp90 by the co-chaperone Sti1. EMBO J 2012; 31: 1518–1528.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Muller P, Ruckova E, Halada P, Coates PJ, Hrstka R, Lane DP et al. C-terminal phosphorylation of Hsp70 and Hsp90 regulates alternate binding to co-chaperones CHIP and HOP to determine cellular protein folding/degradation balances. Oncogene 2013; 32: 3101–3110.

    Article  CAS  PubMed  Google Scholar 

  11. Hajj GNM, Arantes CP, Dias MVS, Roffé M, Costa-Silva B, Lopes MH et al. The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles. Cell Mol Life Sci 2013; 70: 3211–3227.

    Article  CAS  PubMed  Google Scholar 

  12. Zanata SM, Lopes MH, Mercadante AF, Hajj GNM, Chiarini LB, Nomizo R et al. Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J 2002; 21: 3307–3316.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Lopes MH, Hajj GNM, Muras AG, Mancini GL, Castro RMPS, Ribeiro KCB et al. Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J Neurosci 2005; 25: 11330–11339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Li C, Yu S, Nakamura F, Yin S, Xu J, Petrolla AA et al. Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer. J Clin Invest 2009; 119: 2725–2736.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Li C, Yu S, Nakamura F, Pentikainen OT, Singh N, Yin S et al. Pro-prion binds filamin A, facilitating its interaction with integrin 1, and contributes to melanomagenesis. J Biol Chem 2010; 285: 30328–30339.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Li Q-Q, Sun Y-P, Ruan C-P, Xu X-Y, Ge J-H, He J et al. Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival. Cancer Sci 2011; 102: 400–406.

    Article  CAS  PubMed  Google Scholar 

  17. Pan Y . Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB J 2006; 20: 1886–1888.

    Article  CAS  PubMed  Google Scholar 

  18. Kubota H, Yamamoto S, Itoh E, Abe Y, Nakamura A, Izumi Y et al. Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma. Cell Stress Chaperones 2010; 15: 1003–1011.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Ruckova E, Muller P, Nenutil R, Vojtesek B . Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer. Cell Mol Biol Lett 2012; 17: 446–458.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Walsh N, O’Donovan N, Kennedy S, Henry M, Meleady P, Clynes M et al. Identification of pancreatic cancer invasion-related proteins by proteomic analysis. Proteome Sci 2009; 7: 3.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Sun W, Xing B, Sun Y, Du X, Lu M, Hao C et al. Proteome analysis of hepatocellular carcinoma by two-dimensional difference gel electrophoresis: novel protein markers in hepatocellular carcinoma tissues. Mol Cell Proteom 2007; 6: 1798–1808.

    Article  CAS  Google Scholar 

  22. Wang T-H, Chao AA-S, Tsai C-L, Chang C-L, Chen S-H, Lee Y-S et al. Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation. Mol Cell Proteom 2010; 9: 1873–1884.

    Article  CAS  Google Scholar 

  23. Sims JD, McCready J, Jay DG . Extracellular heat shock protein (Hsp)70 and Hsp90α assist in matrix metalloproteinase-2 activation and breast cancer cell migration and invasion. PLoS One 2011; 6: e18848.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Walsh N, Larkin A, Swan N, Conlon K, Dowling P, McDermott R et al. RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 2011; 306: 180–189.

    Article  CAS  PubMed  Google Scholar 

  25. Eustace BK, Jay DG . Extracellular roles for the molecular chaperone, hsp90. Cell Cycle. 2004; 3: 1098–1100.

    Article  CAS  PubMed  Google Scholar 

  26. Tsai C-L, Tsai C-N, Lin C-Y, Chen H-W, Lee Y-S, Chao A et al. Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells. Cell Rep 2012; 2: 283–293.

    Article  CAS  PubMed  Google Scholar 

  27. Wasilewska-Sampaio AP, Santos TG, Lopes MH, Cammarota M, Martins VR . The growth of glioblastoma orthotopic xenografts in nude mice is directly correlated with impaired object recognition memory. Physiol Behav 2013; 123C: 55–61.

    Google Scholar 

  28. Caine C, Mehta MP, Laack NN, Gondi V . Cognitive function testing in adult brain tumor trials: lessons from a comprehensive review. Expert Rev Anticancer Ther 2012; 12: 655–667.

    Article  CAS  PubMed  Google Scholar 

  29. Sy M-S, Altekruse SF, Li C, Lynch CF, Goodman MT, Hernandez BY et al. Association of prion protein expression with pancreatic adenocarcinoma survival in the SEER residual tissue repository. Cancer Biomark 2012; 10: 251–258.

    Article  Google Scholar 

  30. Antonacopoulou AG, Palli M, Marousi S, Dimitrakopoulos F-I, Kyriakopoulou U, Tsamandas AC et al. Prion protein expression and the M129V polymorphism of the PRNP gene in patients with colorectal cancer. Mol Carcinogen 2010; 49: 693–699.

    CAS  Google Scholar 

  31. Antonacopoulou AG, Grivas PD, Skarlas L, Kalofonos M, Scopa CD, Kalofonos HP . POLR2F, ATP6V0A1 and PRNP expression in colorectal cancer: new molecules with prognostic significance? Anticancer Res 2008; 28: 1221–1227.

    CAS  PubMed  Google Scholar 

  32. Pimienta G, Herbert KM, Regan L . A compound that inhibits the HOP–Hsp90 complex formation and has unique killing effects in breast cancer cell lines. Mol Pharm 2011; 8: 2252–2261.

    Article  CAS  PubMed  Google Scholar 

  33. Horibe T, Kohno M, Haramoto M, Ohara K, Kawakami K . Designed hybrid TPR peptide targeting Hsp90 as a novel anticancer agent. J Transl Med 2011; 9: 8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Horibe T, Torisawa A, Kohno M, Kawakami K . Molecular mechanism of cytotoxicity induced by Hsp90-targeted Antp-TPR hybrid peptide in glioblastoma cells. Mol Cancer 2012; 11: 59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Lima FRS, Arantes CP, Muras AG, Nomizo R, Brentani RR, Martins VR . Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation. J Neurochem 2007; 103: 2164–2176.

    Article  CAS  PubMed  Google Scholar 

  36. Barbieri G, Palumbo S, Gabrusiewicz K, Azzalin A, Marchesi N, Spedito A et al. Silencing of cellular prion protein (PrPC) expression by DNA-antisense oligonucleotides induces autophagy-dependent cell death in glioma cells. Autophagy 2011; 7: 840–853.

    Article  CAS  PubMed  Google Scholar 

  37. Yu G, Jiang L, Xu Y, Guo H, Liu H, Zhang Y et al. Silencing prion protein in MDA-MB-435 breast cancer cells leads to pleiotropic cellular responses to cytotoxic stimuli. PLoS One 2012; 7: e48146.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Meslin F, Conforti R, Mazouni C, Morel N, Tomasic G, Drusch F et al. Efficacy of adjuvant chemotherapy according to prion protein expression in patients with estrogen receptor-negative breast cancer. Ann Oncol 2007; 18: 1793–1798.

    Article  CAS  PubMed  Google Scholar 

  39. Willmer T, Contu L, Blatch GL, Edkins AL . Knockdown of Hop downregulates RhoC expression, and decreases pseudopodia formation and migration in cancer cell lines. Cancer Lett 2013; 328: 252–260.

    Article  CAS  PubMed  Google Scholar 

  40. Allhenn D, Boushehri MAS, Lamprecht A . Drug delivery strategies for the treatment of malignant gliomas. Int J Pharm 2012; 436: 299–310.

    Article  CAS  PubMed  Google Scholar 

  41. Quant EC, Wen PY . Novel medical therapeutics in glioblastomas, including targeted molecular therapies, current and future clinical trials. Neuroimaging Clin N Am 2010; 20: 425–448.

    Article  PubMed  Google Scholar 

  42. Joo KM, Kim J, Jin J, Kim M, Seol HJ, Muradov J et al. Patient-specific orthotopic glioblastoma xenograft models recapitulate the histopathology and biology of human glioblastomas in situ. Cell Rep 2013; 3: 260–273.

    Article  CAS  PubMed  Google Scholar 

  43. Santos TG, Silva IR, Costa-Silva B, Lepique AP, Martins VR, Lopes MH . Enhanced neural progenitor/stem cells self-renewal via the interaction of stress-inducible protein 1 with the prion protein. Stem Cells 2011; 29: 1126–1136.

    Article  CAS  PubMed  Google Scholar 

  44. Zhuang D, Liu Y, Mao Y, Gao L, Zhang H, Luan S et al. TMZ-induced PrPc/par-4 interaction promotes the survival of human glioma cells. Int J Cancer 2012; 130: 309–318.

    Article  CAS  PubMed  Google Scholar 

  45. Chen J, Li Y, Yu T-S, McKay RM, Burns DK, Kernie SG et al. A restricted cell population propagates glioblastoma growth after chemotherapy. Nature 2012; 488: 522–526.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Butowski N, Chang SM . Endpoints for clinical trials and revised assessment in neuro-oncology. Curr Opin Neurol 2012; 25: 780–785.

    Article  PubMed  Google Scholar 

  47. Coitinho AS, Lopes MH, Hajj GN, Rossato JI, Freitas AR, Castro CC et al. Short-term memory formation and long-term memory consolidation are enhanced by cellular prion association to stress-inducible protein 1. Neurobiol Dis 2007; 26: 282–290.

    Article  CAS  PubMed  Google Scholar 

  48. Gehring K, Sitskoorn MM, Aaronson NK, Taphoorn MJB . Interventions for cognitive deficits in adults with brain tumours. Lancet Neurol 2008; 7: 548–560.

    Article  PubMed  Google Scholar 

  49. Brown KR, Otasek D, Ali M, McGuffin MJ, Xie W, Devani B et al. NAViGaTOR: Network Analysis, Visualization and Graphing Toronto. Bioinformatics 2009; 25: 3327–3329.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Kononen J, Bubendorf L, Kallioniemi A, Bärlund M, Schraml P, Leighton S et al. Tissue microarrays for high-throughput molecular profiling of tumor specimens. Nat Med 1998; 4: 844–847.

    Article  CAS  PubMed  Google Scholar 

  51. Alvarenga AW, Coutinho-Camillo CM, Rodrigues BR, Rocha RM, Torres LFB, Martins VR et al. A comparison between manual and automated evaluations of tissue microarray patterns of protein expression. J Histochem Cytochem 2013; 61: 272–282.

    Article  PubMed  PubMed Central  Google Scholar 

  52. Lal S, Lacroix M, Tofilon P, Fuller GN, Sawaya R, Lang FF . An implantable guide-screw system for brain tumor studies in small animals. J Neurosurg 2000; 92: 326–333.

    Article  CAS  PubMed  Google Scholar 

  53. Weissert R, Wallström E, Storch MK, Stefferl A, Lorentzen J, Lassmann H et al. MHC haplotype-dependent regulation of MOG-induced EAE in rats. J Clin Invest 1998; 102: 1265–1273.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

This work was supported by Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 09/14027-2, 07/08410-2 and 04/12133-6) and Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq). Fellowships from FAPESP (to TGS) (2009/51653-9), NGQ (2009/51751-0), BC-S (2008/55381-0), BRR (2010-13654-0, 2012/19019-0), APW-S (2010/20796-6), and from Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES) (to APW-S) are gratefully acknowledged. We are thankful for Maria Del Mar Inda and Severino da Silva Ferreira for technical assistance. Drs Maria Dirlei Begnami, Victor Piana de Andrade and Martín Roffe contributed with helpful discussions. We thank the AC Camargo Biobank for providing the astrocytoma samples used in this study.

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Author notes

  1. M H Lopes and T G Santos: These authors contributed equally to this work.

Authors and Affiliations

  1. International Research Center, AC Camargo Cancer Center, São Paulo, Brazil

    M H Lopes, T G Santos, B R Rodrigues, N Queiroz-Hazarbassanov, A P Wasilewska-Sampaio, B Costa-Silva, F A Marchi & V R Martins

  2. Department of Cell and Developmental Biology, Institute of Biomedical Sciences, University of São Paulo,

    M H Lopes

  3. São Paulo, Brazil

    M H Lopes

  4. National Institute for Translational Neuroscience and National Institute of Oncogenomics (CNPq/MCT/FAPESP), São Paulo, Brazil

    M H Lopes, T G Santos, B R Rodrigues, N Queiroz-Hazarbassanov, A P Wasilewska-Sampaio, B Costa-Silva, F A Marchi & V R Martins

  5. Department of Pathology, AC Camargo Cancer Center, São Paulo, Brazil

    I W Cunha

  6. Inter-institutional Grad Program on Bioinformatics, Institute of Mathematics and Statistics, USP—São Paulo University, São Paulo, Brazil

    F A Marchi

  7. Department of Pathology, Federal University of Paraná, Curitiba, Brazil

    L F Bleggi-Torres

  8. Pelé Pequeno Príncipe Research Institute, Curitiba, Brazil

    L F Bleggi-Torres

  9. Department of Neurosurgery, AC Camargo Cancer Center, São Paulo, Brazil

    P I Sanematsu & S H Suzuki

  10. Department of Neurology, School of Medicine, University of São Paulo, Brazil

    S M Oba-Shinjo & S K N Marie

  11. Department of Biochemistry and Molecular Biology, Bio21 Molecular Science and Biotechnology Institute, University of Melbourne, Melbourne, VIC, Australia,

    E Toulmin & A F Hill

  12. Ludwig Institute for Cancer Research, São Paulo, Brazil

    V R Martins

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Lopes, M., Santos, T., Rodrigues, B. et al. Disruption of prion protein–HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene 34, 3305–3314 (2015). https://doi.org/10.1038/onc.2014.261

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