Skip to main content

Advertisement

SpringerLink
Log in

Survivin inhibition by an interacting recombinant peptide, derived from the human ferritin heavy chain, impedes tumor cell growth

  • Original Paper
  • Published:
Journal of Cancer Research and Clinical Oncology Aims and scope Submit manuscript

Abstract

Background

Proteins involved in the aberrant regulation of signaling pathways and their downstream effectors are promising targets for cancer therapy. Survivin is an anti-apoptotic and cell cycle-promoting protein, which is consistently overexpressed in cancer cells. In normal cells, its expression is tightly controlled by signaling pathways and their associated transcriptional activators and repressors. In cancer cells, its expression is enhanced as a consequence of oncogenic signaling. We investigated the potential of a novel, peptide-based survivin inhibitor in breast cancer (SK-BR-3, MDA-MB-468) and glioblastoma (Tu9648) cells. These cells express high levels of survivin.

Materials and methods

We downregulated survivin expression in tumor cells with a lentiviral gene transfer vector encoding a specific shRNA and a recombinant fusion protein, rSip, comprising the FTH1-derived survivin interaction domain, the human thioredoxin and a protein transduction domain.

Results

Downregulation of survivin expression decreased the growth and viability of tumor cells in culture and reduced growth of the cancer cells upon transplantation into immunodeficient mice. rSip selectively targets the anti-apoptotic function of survivin and causes tumor cell death. Non-transformed NIH/3T3 and MCF10A cells remain unaffected.

Conclusions

rSip provides a lead structure for the development of drugs targeting the tumor cell “addiction protein” survivin.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  • Abt AC, Meucci O (2011) Regulation of neuronal ferritin heavy chain, a new player in opiate-induced chemokine dysfunction. J Neuroimmune Pharmacol 6(4):466–476

    Article  PubMed  Google Scholar 

  • Altieri DC (2008) New wirings in the survivin networks. Oncogene 27:6276–6284

    Article  PubMed  CAS  Google Scholar 

  • Altieri DC (2010) Survivin and IAP proteins in cell-death mechanisms. Biochem J 430:199–205

    Article  PubMed  CAS  Google Scholar 

  • Bell DW (2010) Our changing view of the genomic landscape of cancer. J Pathol 220:231–243

    PubMed  CAS  Google Scholar 

  • Bickle MB, Dusserre E, Moncorge O, Bottin H, Colas P (2006) Selection and characterization of large collections of peptide aptamers through optimized yeast two-hybrid procedures. Nat Protoc 1:1066–1091

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Borghouts C, Kunz C, Delis N, Groner B (2008) Monomeric recombinant peptide aptamers are required for efficient intracellular uptake and target inhibition. Mol Cancer Res 6:267–281

    Article  PubMed  CAS  Google Scholar 

  • Borghouts C, Tittmann H, Delis N, Kirchenbauer M, Brill B, Groner B (2010a) The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death. Mol Cancer Res 8:539–553

    Article  PubMed  CAS  Google Scholar 

  • Borghouts C, Tittmann H, Delis N, Kirchenbauer M, Brill B, Groner B (2010b) The intracellular delivery of a recombinant peptide derived from the acidic domain of PIAS3 inhibits STAT3 transactivation and induces tumor cell death. Mol Cancer Res 8:539–553

    Article  PubMed  CAS  Google Scholar 

  • Bourhis E, Hymowitz SG, Cochran AG (2007) The mitotic regulator Survivin binds as a monomer to its functional interactor Borealin. J Biol Chem 282:35018–35023

    Article  PubMed  CAS  Google Scholar 

  • Cencic R, Hall DR, Robert F, Du Y, Min J, Li L, Qui M, Lewis I, Kurtkaya S, Dingledine R, Fu H, Kozakov D, Vajda S, Pelletier J (2011) Reversing chemoresistance by small molecule inhibition of the translation initiation complex eIF4F. Proc Natl Acad Sci USA 108:1046–1051

    Article  PubMed  CAS  Google Scholar 

  • Chowdhury S, Howell GM, Teggart CA, Chowdhury A, Person JJ, Bowers DM, Brattain MG (2011) The histone deacetylase inhibitor belinostat represses survivin expression through reactivation of TGF{beta} receptor II leading to cancer cell death. J Biol Chem 286(35):30937–30948

    Article  PubMed  CAS  Google Scholar 

  • Davidson BL, McCray PB Jr (2011) Current prospects for RNA interference-based therapies. Nat Rev Genet 12:329–340

    Article  PubMed  CAS  Google Scholar 

  • Dean EJ, Ranson M, Blackhall F, Dive C (2007) X-linked inhibitor of apoptosis protein as a therapeutic target. Expert Opin Ther Targets 11:1459–1471

    Article  PubMed  CAS  Google Scholar 

  • Demaison C, Parsley K, Brouns G, Scherr M, Battmer K, Kinnon C, Grez M, Thrasher AJ (2002) High-level transduction and gene expression in hematopoietic repopulating cells using a human immunodeficiency [correction of immunodeficiency] virus type 1-based lentiviral vector containing an internal spleen focus forming virus promoter. Hum Gene Ther 13:803–813

    Article  PubMed  CAS  Google Scholar 

  • Ding L, Ellis MJ, Li S, Larson DE, Chen K, Wallis JW, Harris CC, McLellan MD, Fulton RS, Fulton LL, Abbott RM, Hoog J, Dooling DJ, Koboldt DC, Schmidt H, Kalicki J, Zhang Q, Chen L, Lin L, Wendl MC, McMichael JF, Magrini VJ, Cook L, McGrath SD, Vickery TL, Appelbaum E, Deschryver K, Davies S, Guintoli T, Crowder R, Tao Y, Snider JE, Smith SM, Dukes AF, Sanderson GE, Pohl CS, Delehaunty KD, Fronick CC, Pape KA, Reed JS, Robinson JS, Hodges JS, Schierding W, Dees ND, Shen D, Locke DP, Wiechert ME, Eldred JM, Peck JB, Oberkfell BJ, Lolofie JT, Du F, Hawkins AE, O’Laughlin MD, Bernard KE, Cunningham M, Elliott G, Mason MD, Thompson DM Jr, Ivanovich JL, Goodfellow PJ, Perou CM, Weinstock GM, Aft R, Watson M, Ley TJ, Wilson RK, Mardis ER (2010) Genome remodelling in a basal-like breast cancer metastasis and xenograft. Nature 464:999–1005

    Article  PubMed  CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  • Felsher DW (2008) Reversing cancer from inside and out: oncogene addiction, cellular senescence, and the angiogenic switch. Lymphat Res Biol 6:149–154

    Article  PubMed  Google Scholar 

  • Ferreira C, Bucchini D, Martin ME, Levi S, Arosio P, Grandchamp B, Beaumont C (2000) Early embryonic lethality of H ferritin gene deletion in mice. J Biol Chem 275:3021–3024

    Article  PubMed  CAS  Google Scholar 

  • Fukuda S, Pelus LM (2006) Survivin, a cancer target with an emerging role in normal adult tissues. Mol Cancer Ther 5:1087–1098

    Article  PubMed  CAS  Google Scholar 

  • 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 8:808–815

    PubMed  CAS  Google Scholar 

  • Gao Y, Zhang H, Zhang M, Yu X, Kong W, Zha X, Wu Y (2010) N-terminal deletion effects of human survivin on dimerization and binding to Smac/DIABLO in vitro. J Phys Chem B 114:15656–15662

    Article  PubMed  CAS  Google Scholar 

  • Hentze MW, Muckenthaler MU, Andrews NC (2004) Balancing acts: molecular control of mammalian iron metabolism. Cell 117:285–297

    Article  PubMed  CAS  Google Scholar 

  • Hintze KJ, Theil EC (2006) Cellular regulation and molecular interactions of the ferritins. Cell Mol Life Sci 63:591–600

    Article  PubMed  CAS  Google Scholar 

  • Imming P, Sinning C, Meyer A (2006) Drugs, their targets and the nature and number of drug targets. Nat Rev Drug Discov 5:821–834

    Article  PubMed  CAS  Google Scholar 

  • Islam A, Kageyama H, Takada N, Kawamoto T, Takayasu H, Isogai E, Ohira M, Hashizume K, Kobayashi H, Kaneko Y, Nakagawara A (2000) High expression of Survivin, mapped to 17q25, is significantly associated with poor prognostic factors and promotes cell survival in human neuroblastoma. Oncogene 19:617–623

    Article  PubMed  CAS  Google Scholar 

  • Kelly RJ, Lopez-Chavez A, Citrin D, Janik JE, Morris JC (2011) Impacting tumor cell-fate by targeting the inhibitor of apoptosis protein survivin. Mol Cancer 10:35

    Article  PubMed  CAS  Google Scholar 

  • Knovich MA, Storey JA, Coffman LG, Torti SV, Torti FM (2009) Ferritin for the clinician. Blood Rev 23:95–104

    Article  PubMed  CAS  Google Scholar 

  • LaCasse EC, Mahoney DJ, Cheung HH, Plenchette S, Baird S, Korneluk RG (2008) IAP-targeted therapies for cancer. Oncogene 27:6252–6275

    Article  PubMed  CAS  Google Scholar 

  • Li R, Luo C, Mines M, Zhang J, Fan GH (2006) Chemokine CXCL12 induces binding of ferritin heavy chain to the chemokine receptor CXCR4, alters CXCR4 signaling, and induces phosphorylation and nuclear translocation of ferritin heavy chain. J Biol Chem 281:37616–37627

    Article  PubMed  CAS  Google Scholar 

  • Li L, Fang CJ, Ryan JC, Niemi EC, Lebron JA, Bjorkman PJ, Arase H, Torti FM, Torti SV, Nakamura MC, Seaman WE (2010) Binding and uptake of H-ferritin are mediated by human transferrin receptor-1. Proc Natl Acad Sci USA 107:3505–3510

    Article  PubMed  CAS  Google Scholar 

  • Lladser A, Sanhueza C, Kiessling R, Quest AF (2011) Is survivin the potential Achilles’ heel of cancer? Adv Cancer Res 111:1–37

    Article  PubMed  CAS  Google Scholar 

  • Luo J, Solimini NL, Elledge SJ (2009) Principles of cancer therapy: oncogene and non-oncogene addiction. Cell 136:823–837

    Article  PubMed  CAS  Google Scholar 

  • Mesri M, Wall NR, Li J, Kim RW, Altieri DC (2001) Cancer gene therapy using a survivin mutant adenovirus. J Clin Invest 108:981–990

    PubMed  CAS  Google Scholar 

  • Mita AC, Mita MM, Nawrocki ST, Giles FJ (2008) Survivin: key regulator of mitosis and apoptosis and novel target for cancer therapeutics. Clin Cancer Res 14:5000–5005

    Article  PubMed  CAS  Google Scholar 

  • Moellering RE, Cornejo M, Davis TN, Del Bianco C, Aster JC, Blacklow SC, Kung AL, Gilliland DG, Verdine GL, Bradner JE (2009) Direct inhibition of the NOTCH transcription factor complex. Nature 462:182–188

    Article  PubMed  CAS  Google Scholar 

  • Montazeri Aliabadi H, Landry B, Mahdipoor P, Uludag H (2011) Induction of apoptosis by survivin silencing through siRNA delivery in a human breast cancer cell line. Mol Pharm 8(5):1821–1830

    Article  PubMed  Google Scholar 

  • Morell M, Czihal P, Hoffmann R, Otvos L, Aviles FX, Ventura S (2008a) Monitoring the interference of protein–protein interactions in vivo by bimolecular fluorescence complementation: the DnaK case. Proteomics 8:3433–3442

    Article  PubMed  CAS  Google Scholar 

  • Morell M, Espargaro A, Aviles FX, Ventura S (2008b) Study and selection of in vivo protein interactions by coupling bimolecular fluorescence complementation and flow cytometry. Nat Protoc 3:22–33

    Article  PubMed  CAS  Google Scholar 

  • Naldini L, Blomer U, Gallay P, Ory D, Mulligan R, Gage FH, Verma IM, Trono D (1996) In vivo gene delivery and stable transduction of nondividing cells by a lentiviral vector. Science 272:263–267

    Article  PubMed  CAS  Google Scholar 

  • Oikawa T, Unno Y, Matsuno K, Sawada J, Ogo N, Tanaka K, Asai A (2010) Identification of a small-molecule inhibitor of the interaction between survivin and Smac/DIABLO. Biochem Biophys Res Commun 393:253–258

    Article  PubMed  CAS  Google Scholar 

  • Park E, Gang EJ, Hsieh YT, Schaefer P, Chae S, Klemm L, Huantes S, Loh M, Conway EM, Kang ES, Koo HH, Hofmann WK, Heisterkamp N, Pelus L, Keerthivasan G, Crispino J, Kahn M, Muschen M, Kim YM (2011) Targeting survivin overcomes drug resistance in acute lymphoblastic leukemia. Blood 118(8):2191–2199

    Article  PubMed  CAS  Google Scholar 

  • Russ AP, Lampel S (2005) The druggable genome: an update. Drug Discov Today 10:1607–1610

    Article  PubMed  Google Scholar 

  • Ryan BM, O’Donovan N, Duffy MJ (2009) Survivin: a new target for anti-cancer therapy. Cancer Treat Rev 35:553–562

    Article  PubMed  CAS  Google Scholar 

  • Scott JD, Pawson T (2009) Cell signaling in space and time: where proteins come together and when they’re apart. Science 326:1220–1224

    Article  PubMed  CAS  Google Scholar 

  • Sharma SV, Settleman J (2010) Exploiting the balance between life and death: targeted cancer therapy and “oncogenic shock”. Biochem Pharmacol 80:666–673

    Article  PubMed  CAS  Google Scholar 

  • Sioud M (2011) Promises and challenges in developing RNAi as a research tool and therapy. Methods Mol Biol 703:173–187

    Article  PubMed  CAS  Google Scholar 

  • Stein A, Pache RA, Bernado P, Pons M, Aloy P (2009) Dynamic interactions of proteins in complex networks: a more structured view. FEBS J 276:5390–5405

    Article  PubMed  CAS  Google Scholar 

  • Vader G, Kauw JJ, Medema RH, Lens SM (2006) Survivin mediates targeting of the chromosomal passenger complex to the centromere and midbody. EMBO Rep 7:85–92

    Article  PubMed  CAS  Google Scholar 

  • Verdine GL, Walensky LD (2007) The challenge of drugging undruggable targets in cancer: lessons learned from targeting BCL-2 family members. Clin Cancer Res 13:7264–7270

    Article  PubMed  CAS  Google Scholar 

  • Wang T, Wei J, Qian X, Ding Y, Yu L, Liu B (2008) Gambogic acid, a potent inhibitor of survivin, reverses docetaxel resistance in gastric cancer cells. Cancer Lett 262:214–222

    Article  PubMed  CAS  Google Scholar 

  • Wang W, Di X, Torti SV, Torti FM (2010) Ferritin H induction by histone deacetylase inhibitors. Biochem Pharmacol 80:316–324

    Article  PubMed  CAS  Google Scholar 

  • Yamamoto H, Ngan CY, Monden M (2008) Cancer cells survive with survivin. Cancer Sci 99:1709–1714

    Article  PubMed  CAS  Google Scholar 

  • Yan H, Thomas J, Liu T, Raj D, London N, Tandeski T, Leachman SA, Lee RM, Grossman D (2006) Induction of melanoma cell apoptosis and inhibition of tumor growth using a cell-permeable Survivin antagonist. Oncogene 25:6968–6974

    Article  PubMed  CAS  Google Scholar 

  • Yonesaka K, Tamura K, Kurata T, Satoh T, Ikeda M, Fukuoka M, Nakagawa K (2006) Small interfering RNA targeting survivin sensitizes lung cancer cell with mutant p53 to adriamycin. Int J Cancer 118:812–820

    Article  PubMed  CAS  Google Scholar 

  • Yoo JW, Irvine DJ, Discher DE, Mitragotri S (2011) Bio-inspired, bioengineered and biomimetic drug delivery carriers. Nat Rev Drug Discov 10:521–535

    Article  PubMed  CAS  Google Scholar 

  • Zufferey R, Nagy D, Mandel RJ, Naldini L, Trono D (1997) Multiply attenuated lentiviral vector achieves efficient gene delivery in vivo. Nat Biotechnol 15:871–875

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

We thank Nancy Hynes (Friedrich Miescher Institute, Basel, Switzerland), Donat Kögel and Jakob Weissenberger (Neuroscience Center, Goethe University, Frankfurt, Germany) and Manuel Grez (Georg-Speyer-Haus, Frankfurt, Germany) for providing tumor cell lines and Axel Weber, Vida Vafaizadeh and Nadja Bednorz (Georg-Speyer-Haus, Frankfurt, Germany) for support and helpful discussions. This study was supported by the Deutsche Forschungsgemeinschaft (Bonn, Germany) within the graduate study program GRK 1172 “Biologicals”.

Conflict of interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

  1. Georg-Speyer-Haus, Institute for Biomedical Research, Paul Ehrlich Str. 42-44, 60596, Frankfurt am Main, Germany

    Astrid Weiss, Boris Brill, Corina Borghouts, Natalia Delis, Laura Mack & Bernd Groner

Authors
  1. Astrid Weiss
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Boris Brill
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Corina Borghouts
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Natalia Delis
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Laura Mack
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Bernd Groner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Bernd Groner.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Weiss, A., Brill, B., Borghouts, C. et al. Survivin inhibition by an interacting recombinant peptide, derived from the human ferritin heavy chain, impedes tumor cell growth. J Cancer Res Clin Oncol 138, 1205–1220 (2012). https://doi.org/10.1007/s00432-012-1195-1

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00432-012-1195-1

Keywords

Search

Navigation