Skip to main content
SpringerLink
Log in

Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells

Clinical & Experimental Metastasis Aims and scope Submit manuscript

Abstract

Colorectal cancer (CRC) is one of the most frequently diagnosed malignancies. The generation of conventional treatments has improved, but approximately 50 % of patients with CRC who undergo potentially curative surgery ultimately relapse and die, usually as a consequence of metastatic disease. Our previous findings showed that engagement of the cellular prion protein (PrPC) to its ligand HSP70/90 heat shock organizing protein (HOP) induces proliferation of glioblastomas. In addition, PrPC has been described as an important modulator of colorectal tumor growth. Here, we investigated the biological relevance of the PrPC-HOP interaction in CRC cells. We demonstrate that HOP induced the migration and invasion of CRC cell lines in a PrPC-dependent manner and that phosphorylation of the ERK1/2 pathway is a downstream mediator of these effects. Additionally, we show that a HOP peptide with the ability to bind PrPC and abolish the PrPC-HOP interaction inhibited the migration and invasion of CRC cells. Together, these data indicate that the disruption of the PrPC-HOP complex could be a potential therapeutic target for modulating the migratory and invasive cellular properties that lead to metastatic CRC.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

We’re sorry, something doesn't seem to be working properly.

Please try refreshing the page. If that doesn't work, please contact support so we can address the problem.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

References

  1. Weigelt B, Peterse JL, van’t Veer LJ (2005) Breast cancer metastasis: markers and models. Nat Rev Cancer 5:591–602. doi:10.1038/nrc1670

    Article  CAS  PubMed  Google Scholar 

  2. Bravo-Cordero JJ, Hodgson L, Condeelis J (2012) Directed cell invasion and migration during metastasis. Curr Opin Cell Biol 24:277–283. doi:10.1016/j.ceb.2011.12.004

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell 144:646–674. doi:10.1016/j.cell.2011.02.013

    Article  CAS  PubMed  Google Scholar 

  4. Christofori G (2006) New signals from the invasive front. Nature 441:444–450. doi:10.1038/nature04872

    Article  CAS  PubMed  Google Scholar 

  5. Kramer N, Walzl A, Unger C, Rosner M, Krupitza G, Hengstschläger M et al (2013) In vitro cell migration and invasion assays. Mutat Res 752:10–24. doi:10.1016/j.mrrev.2012.08.001

    Article  CAS  PubMed  Google Scholar 

  6. Friedl P, Alexander S (2011) Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147:992–1009. doi:10.1016/j.cell.2011.11.016

    Article  CAS  PubMed  Google Scholar 

  7. Siegel R, Desantis C, Jemal A (2014) Colorectal cancer statistics, 2014. CA Cancer J Clin 64:104–117. doi:10.3322/caac.21220

    Article  PubMed  Google Scholar 

  8. Boyle P, Ferlay J (2005) Cancer incidence and mortality in Europe, 2004. Ann Oncol 16:481–488. doi:10.1093/annonc/mdi098

    Article  CAS  PubMed  Google Scholar 

  9. Lopes MH, Santos TG, Rodrigues BR, Queiroz-Hazarbassanov N, Cunha IW, Wasilewska-Sampaio AP et al (2014) Disruption of prion protein-HOP engagement impairs glioblastoma growth and cognitive decline and improves overall survival. Oncogene 34:3305–3314. doi:10.1038/onc.2014.261

    Article  PubMed  Google Scholar 

  10. Pan Y, Zhao L, Liang JP (2006) Cellular prion protein promotes invasion and metastasis of gastric cancer. FASEB 20:1886–1888. doi:10.1096/fj.06-6138fje

    Article  CAS  Google Scholar 

  11. Meslin F, Hamaï A, Gao P, Jalil A, Cahuzac N, Chouaib S et al (2007) Silencing of prion protein sensitizes breast adriamycin-resistant carcinoma cells to TRAIL-mediated cell death. Cancer Res 67:10910–10919. doi:10.1158/0008-5472.CAN-07-0512

    Article  CAS  PubMed  Google Scholar 

  12. Kikuchi Y, Kakeya T, Yamazaki T, Takekida K, Nakamura N, Matsuda H et al (2002) G1-dependent prion protein expression in human glioblastoma cell line T98G. Biol Pharm Bull 25:728–733. doi:10.1248/bpb.25.728

    Article  CAS  PubMed  Google Scholar 

  13. Wang Q, Qian J, Wang F, Ma Z (2012) Cellular prion protein accelerates colorectal cancer metastasis via the Fyn-SP1-SATB1 axis. Oncol Rep 28:2029–2034. doi:10.3892/or.2012.2025

    CAS  PubMed  Google Scholar 

  14. Li C, Yu S, Nakamura F, Yin S, Xu J, Petrolla AA et al (2009) Binding of pro-prion to filamin A disrupts cytoskeleton and correlates with poor prognosis in pancreatic cancer. J Clin Investig 119:2725–2736. doi:10.1172/JCI39542

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Sy MS, Li C, Yu S, Xin W (2010) The fatal attraction between pro-prion and filamin A: prion as a marker in human cancers. Biomark Med 4:453–464. doi:10.2217/bmm.10.14

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Sauer H, Dagdanova A, Hescheler J, Wartenberg M (1999) Redox-regulation of intrinsic prion expression in multicellular prostate tumor spheroids. Free Radic Biol Med 27:1276–1283. doi:10.1016/S0891-5849(99)00164-1

    Article  CAS  PubMed  Google Scholar 

  17. Li QQ, Sun YP, Ruan CP, Xu XY, Ge JH, He J et al (2011) Cellular prion protein promotes glucose uptake through the Fyn-HIF-2α-Glut1 pathway to support colorectal cancer cell survival. Cancer Sci 102:400–406. doi:10.1111/j.1349-7006.2010.01811.x

    Article  CAS  PubMed  Google Scholar 

  18. McEwan JF, Windsor ML, Cullis-Hill SD (2009) Antibodies to prion protein inhibit human colon cancer cell growth. Tumour Biol 30:141–147. doi:10.1159/000225243

    Article  CAS  PubMed  Google Scholar 

  19. Zhou L, Shang Y, Liu C, Li J, Hu H, Liang C et al (2014) Overexpression of PrPc, combined with MGr1-Ag/37LRP, is predictive of poor prognosis in gastric cancer. Int J Cancer 135:2329–2337. doi:10.1002/ijc.28883

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Chieng CK, Say YH (2015) Cellular prion protein contributes to LS 174T colon cancer cell carcinogenesis by increasing invasiveness and resistance against doxorubicin-induced apoptosis. Tumour Biol. doi:10.1007/s13277-015-3530-z

    PubMed  Google Scholar 

  21. Cheng Y, Tao L, Xu J, Li Q, Yu J, Jin Y et al (2014) CD44/cellular prion protein interact in multidrug resistant breast cancer cells and correlate with responses to neoadjuvant chemotherapy in breast cancer patients. Mol Carcinog 53:686–697. doi:10.1002/mc.22021

    Article  CAS  PubMed  Google Scholar 

  22. Muras AG, Hajj GN, Ribeiro KB, Nomizo R, Nonogaki S, Chammas R et al (2009) Prion protein ablation increases cellular aggregation and embolization contributing to mechanisms of metastasis. Int J Cancer 125:1523–1531. doi:10.1002/ijc.24425

    Article  CAS  PubMed  Google Scholar 

  23. Zanata SM, Lopes MH, Mercadante AF, Hajj GN, Chiarini LB, Nomizo R et al (2002) Stress-inducible protein 1 is a cell surface ligand for cellular prion that triggers neuroprotection. EMBO J 21:3307–3316. doi:10.1093/emboj/cdf325

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Song Y, Masison DC (2005) Independent regulation of HSP70 and HSP90 chaerones by HSP70/HSP90-organizing protein STI1 (HOP1). J Biol Chem 280:34178–34185. doi:10.1074/jbc.M505420200

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Lassle M, Blatch GL, Kundra V, Takatori T, Zetter BR (1997) Stress-inducible, murine protein mSTI1. Characterization of binding domains for heat shock proteins and in vitro phosphorylation by different kinases. J Biol Chem 272:1876–1884. doi:10.1074/jbc.272.3.1876

    Article  CAS  PubMed  Google Scholar 

  26. Soares IN, Caetano FA, Pinder J, Rodrigues BR, Beraldo FH, Ostapchenko VG et al (2013) Regulation of stress-inducible phosphoprotein 1 nuclear retention by protein inhibitor of activated STAT PIAS1. Mol Cell Proteomics 12:3253–3270. doi:10.1074/mcp.M113.031005

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Hajj GN, Arantes CP, Dias MV, Roffé M, Costa-Silva B, Lopes MH et al (2013) The unconventional secretion of stress-inducible protein 1 by a heterogeneous population of extracellular vesicles. Cell Mol Life Sci 70:3211–3227. doi:10.1007/s00018-013-1328-y

    Article  CAS  PubMed  Google Scholar 

  28. Lima FR, Arantes CP, Muras AG, Nomizo R, Brentani RR, Martins VR (2007) Cellular prion protein expression in astrocytes modulates neuronal survival and differentiation. J Neurochem 103:2164–2176. doi:10.1111/j.1471-4159.2007.04904.x

    Article  CAS  PubMed  Google Scholar 

  29. Eustace BK, Jay DG (2004) Extracellular roles for the molecular chaperone, hsp90. Cell Cycle 3:1098–1100. doi:10.4161/cc.3.9.1088

    Article  CAS  PubMed  Google Scholar 

  30. Tsai CL, Tsai CN, Lin CY, Chen HW, Lee YS, Chao A et al (2012) Secreted stress-induced phosphoprotein 1 activates the ALK2-SMAD signaling pathways and promotes cell proliferation of ovarian cancer cells. Cell Rep 2:283–293. doi:10.1016/j.celrep.2012.07.002

    Article  CAS  PubMed  Google Scholar 

  31. Erlich RB, Kahn SA, Lima FR, Muras AG, Martins RA, Linden R et al (2007) STI1 promotes glioma proliferation through MAPK and PI3K pathways. Glia 55:1690–1698. doi:10.1002/glia.20579

    Article  PubMed  Google Scholar 

  32. Fonseca AC, Romão L, Amaral RF, Assad Kahn S, Lobo D, Martins S et al (2012) Microglial stress inducible protein 1 promotes proliferation and migration in human glioblastoma cells. Neuroscience 200:130–141. doi:10.1016/j.neuroscience.2011.10.025

    Article  PubMed  Google Scholar 

  33. Ruckova E, Muller P, Nenutil R, Vojtesek B (2012) Alterations of the Hsp70/Hsp90 chaperone and the HOP/CHIP co-chaperone system in cancer. Cell Mol Biol Lett 17:446–458. doi:10.2478/s11658-012-0021-8

    Article  CAS  PubMed  Google Scholar 

  34. Kubota H, Yamamoto S, Itoh E, Abe Y, Nakamura A, Izumi Y et al (2010) Increased expression of co-chaperone HOP with HSP90 and HSC70 and complex formation in human colonic carcinoma. Cell Stress Chaperones 15:1003–1011. doi:10.1007/s12192-010-0211-0

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Walsh N, O’Donovan N, Kennedy S, Henry M, Meleady P, Clynes M et al (2009) Identification of pancreatic cancer invasion-related proteins by proteomic analysis. Proteome Sci 7:3. doi:10.1186/1477-5956-7-3

    Article  PubMed  PubMed Central  Google Scholar 

  36. Walsh N, Larkin A, Swan N, Conlon K, Dowling P, McDermott R et al (2011) RNAi knockdown of Hop (Hsp70/Hsp90 organising protein) decreases invasion via MMP-2 down regulation. Cancer Lett 306:180–189. doi:10.1016/j.canlet.2011.03.004

    Article  CAS  PubMed  Google Scholar 

  37. Wang TH, Chao A, Tsai CL, Chang CL, Chen SH, Lee YS et al (2010) Stress-induced phosphoprotein 1 as a secreted biomarker for human ovarian cancer promotes cancer cell proliferation. Mol Cell Proteomics 9:1873–1884. doi:10.1074/mcp.M110.000802

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Wang H, Ye Y, Pan SY, Zhu GY, Li YW, Fong DW et al (2011) Proteomic identification of proteins involved in the anticancer activities of oridonin in HepG2 cells. Phytomedicine 18:163–169. doi:10.1016/j.phymed.2010.06.011

    Article  CAS  PubMed  Google Scholar 

  39. Santos TG, Silva IR, Costa-Silva B, Lepique AP, Martins VR, Lopes MH (2011) Enhanced neural progenitor/stem cells self-renewal via the interaction of stress-inducible protein 1 with the prion protein. Stem Cells 29:1126–1136. doi:10.1002/stem.664

    Article  CAS  PubMed  Google Scholar 

  40. Antonacopoulou AG, Grivas PD, Skarlas L, Kalofonos M, Scopa CD, Kalofonos HP (2008) POLR2F, ATP6V0A1 and PRNP expression in colorectal cancer: new molecules with prognostic significance? Anticancer Res 28:1221–1227. doi:10.1186/1471-2350-12-156

    CAS  PubMed  Google Scholar 

  41. Murray GI, Telfer CM, Melvin WT, inventors Markers for colorectal cancer. United States Patent Application Publication 2006; http://www.freepatentsonline.com/20060188883.pdf

  42. Eustace BK, Sakurai T, Stewart JK, Yimlamai D, Unger C, Zehetmeier C et al (2004) Functional proteomic screens reveal an essential extracellular role for hsp90 alpha in cancer cell invasiveness. Nat Cell Biol 6:507–514. doi:10.1038/ncb1131

    Article  CAS  PubMed  Google Scholar 

  43. Arantes C, Nomizo R, Lopes MH, Hajj GN, Lima FR, Martins VR (2009) Prion protein and its ligand stress inducible protein 1 regulate astrocyte development. Glia 57:1439–1449. doi:10.1002/glia.20861

    Article  PubMed  Google Scholar 

  44. Lopes MH, Hajj GN, Muras AG, Mancini GL, Castro RM, Ribeiro KC et al (2005) Interaction of cellular prion and stress-inducible protein 1 promotes neuritogenesis and neuroprotection by distinct signaling pathways. J Neurosci 25:11330–11339. doi:10.1523/JNEUROSCI.2313-05.2005

    Article  CAS  PubMed  Google Scholar 

  45. Santos TG, Beraldo FH, Hajj GN, Lopes MH, Roffe M, Lupinacci FC et al (2013) Laminin-γ1 chain and stress inducible protein 1 synergistically mediate PrPC-dependent axonal growth via Ca2+ mobilization in dorsal root ganglia neurons. J Neurochem 124:210–223. doi:10.1111/jnc.12091

    Article  CAS  PubMed  Google Scholar 

  46. Linden R, Martins VR, Prado MA, Cammarota M, Izquierdo I, Brentani RR (2008) Physiology of the prion protein. Physiol Rev 88:673–728. doi:10.1152/physrev.00007.2007

    Article  CAS  PubMed  Google Scholar 

  47. Caetano FA, Lopes MH, Hajj GN, Machado CF, Pinto Arantes C, Magalhães AC et al (2008) Endocytosis of prion protein is required for ERK1/2 signaling induced by stress-inducible protein 1. J Neurosci 28:6691–6702. doi:10.1523/JNEUROSCI.1701-08.2008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Chen HC, Zhu YT, Chen SY, Tseng SC (2012) Wnt signaling induces epithelial–mesenchymal transition with proliferation in ARPE-19 cells upon loss of contact inhibition. Lab Investig 92:676–687. doi:10.1038/labinvest.2011.201

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Funding

Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2009/14027‐2) and National Institute for Science and Technology in Oncogenomics (INCITO). TCSL (11/18718-0), FSG (12/23285-8), MVSD (10/19200-1), GPO (13/26097-0) and BLT (11/20853-2) received fellowships from FAPESP.

Author information

Author notes

  1. Bruno Costa-Silva

    Present address: Champalimaud Research, Champalimaud Centre for the Unknown, Av. Brasilia, Doca de Pedrouços, 1400-038, Lisbon, Portugal

Authors and Affiliations

  1. International Research Center, A.C.Camargo Cancer Center, Rua Taguá, 440 – Liberdade, São Paulo, SP, 01508-010, Brazil

    Tonielli Cristina Sousa de Lacerda, Bruno Costa-Silva, Fernanda Salgueiredo Giudice, Marcos Vinicios Salles Dias, Gabriela Pintar de Oliveira, Bianca Luise Teixeira, Tiago Goss dos Santos & Vilma Regina Martins

  2. Department of Biochemistry, Institute of Chemistry, University of São Paulo (USP), Av. Prof. Lineu Prestes, 748 - Cidade Universitária, São Paulo, SP, 05508-000, Brazil

    Tonielli Cristina Sousa de Lacerda

  3. Children’s Cancer and Blood Foundation Laboratories, Departments of Pediatrics, and Cell and Developmental Biology, Drukier Institute for Children’s Health, Meyer Cancer Center, Weill Cornell Medical College, New York, NY, 10021, USA

    Bruno Costa-Silva

Authors
  1. Tonielli Cristina Sousa de Lacerda
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Bruno Costa-Silva
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Fernanda Salgueiredo Giudice
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Marcos Vinicios Salles Dias
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Gabriela Pintar de Oliveira
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bianca Luise Teixeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Tiago Goss dos Santos
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Vilma Regina Martins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Vilma Regina Martins.

Ethics declarations

Conflict of Interest

The authors declare no conflict of interest.

Electronic supplementary material

Below is the link to the electronic supplementary material.

10585_2016_9788_MOESM1_ESM.tif

Supplementary material 1 (TIFF 664 kb). (A) Migration and (B) Invasion assays in WiDr and HCT8 cell lines. Cells were incubated on the top of boyden chambers coated with matrigel®; Serum-free DMEM or DMEM + 10 % FBS were used as chemoattractants. Data represent the average of at least four independent experiments ± standard error. [*p < 0.05 by Student’s t test]. (C) BrdU proliferation assay performed in WiDr CRC cells in conditions that mimicked the migration/invasion experiments. Cells were plated in 96 well plates and treated with recombinant HOP (5 µM) or 10 % FBS, a condition treated with 10 % FBS for 48 h was also included as positive control. Graph shows the levels of BrdUincorporation in relation to control, non-treated with HOP or FBS, and represents the average of at least four independent experiments ± standard error.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

de Lacerda, T.C.S., Costa-Silva, B., Giudice, F.S. et al. Prion protein binding to HOP modulates the migration and invasion of colorectal cancer cells. Clin Exp Metastasis 33, 441–451 (2016). https://doi.org/10.1007/s10585-016-9788-8

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10585-016-9788-8

Keywords

Search

Navigation