Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Original Paper
  • Published:

siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells

Oncogene volume 22, pages 5938–5945 (2003)Cite this article

Abstract

The targeted inhibition of antiapoptotic factors in tumour cells may provide a rational approach towards the development of novel anticancer therapies. Using human papillomavirus (HPV)-transformed cells as a model system, we investigated if RNA interference (RNAi)-mediated gene silencing can be employed in order to overcome the apoptosis resistance of cancer cells. We found that both vector-borne and synthetic small interfering (si)RNAs, specifically directed against the antiapoptotic HPV E6 oncogene, restored dormant tumour suppressor pathways in HPV-positive cancer cells that are otherwise inactive in the presence of E6. This ultimately resulted in massive apoptotic cell death, selectively in HPV-positive tumour cells. These findings show that RNAi provides a powerful molecular strategy to inactivate intracellular E6 function efficiently. Moreover, they define E6 as a most promising therapeutic target to eliminate HPV-positive tumour cells specifically by RNAi. Thus, by sequence-specific targeting of antiapoptotic genes, siRNAs may be developed into novel therapeutics that can efficiently correct the apoptosis deficiency of cancer cells.

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1
Figure 2
Figure 3
Figure 4
Figure 5

Similar content being viewed by others

References

  • Agami R . (2002). Curr. Opin. Chem. Biol., 6, 829–834.

  • Brummelkamp TR, Bernards R and Agami R . (2002a). Cancer Cell, 2, 243–247.

  • Brummelkamp TR, Bernards R and Agami R . (2002b). Science, 296, 550–553.

  • Butz K, Denk C, Ullmann A, Scheffner M and Hoppe-Seyler F . (2000). Proc. Natl. Acad. Sci. USA, 97, 6693–6697.

  • Butz K, Geisen C, Ullmann A, Zentgraf H and Hoppe-Seyler F . (1998). Oncogene, 17, 781–787.

  • Butz K, Shahabeddin L, Geisen C, Spitkovsky D, Ullmann A and Hoppe-Seyler F . (1995). Oncogene, 10, 927–936.

  • Chen C and Okayama H . (1987). Mol. Cell. Biol., 7, 2745–2752.

  • Chomczynski P and Sacchi N . (1987). Anal. Biochem., 162, 156–159.

  • Cole ST and Danos O . (1987). J. Mol. Biol., 193, 599–608.

  • Elbashir SM, Harboth J, Lendeckel W, Yalcin A, Weber K and Tuschl T . (2001). Nature, 411, 494–498.

  • Elbashir SM, Harboth J, Weber K and Tuschl T . (2002). Methods, 26, 199–213.

  • El-Deiry WS, Tokino T, Velculescu VE, Parsons R, Trent JM, Lin D, Mercer WE, Kinzler KW and Vogelstein B . (1993). Cell, 75, 817–825.

  • Evan GI and Vousden KH . (2001). Nature, 411, 342–348.

  • Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE and Mello CC . (1998). Nature, 391, 806–811.

  • Fulda S, Wick W, Weller M and Debatin M . (2002). Nat. Med., 8, 808–815.

  • Funk WD, Pak DT, Karas RH, Wright WE and Shay JW . (1992). Mol. Cell. Biol., 12, 2866–2871.

  • Goodwin EC and DiMaio D . (2000). Proc. Natl. Acad. Sci. USA, 97, 12513–12518.

  • Hoppe-Seyler F and Butz K . (1999). Anticancer Res., 19, 4747–4758.

  • Igney FH and Krammer PH . (2002). Nat. Rev. Cancer, 2, 277–288.

  • Jaque J-M, Triques K and Stevenson M . (2002). Nature, 418, 435–438.

  • Jiang M and Milner J . (2002). Oncogene, 21, 6041–6048.

  • Lee NS, Dohjima T, Bauer G, Li H, Li M-J, Ehsani A, Salvaterra P and Rossi J . (2002). Nat. Biotechnol., 19, 500–505.

  • Mantovani F and Banks L . (2001). Oncogene, 20, 7874–7887.

  • Mittnacht S . (1998). Curr. Opin. Genet. Dev., 8, 21–27.

  • Morris MC, Chaloin L, Heitz F and Divita G . (2000). Curr. Opin. Biotechnol., 11, 461–466.

  • Münger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M and Zacny VL . (2001). Oncogene, 20, 7888–7898.

  • Nicholson DW . (2000). Nature, 407, 810–816.

  • Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee S-K, Collman RG, Lieberman J, Shankar P and Sharp PA . (2002). Nat. Med., 8, 681–686.

  • Paddison PJ and Hannon GJ . (2002). Cancer Cell, 2, 17–23.

  • Pan H and Griep AE . (1994). Genes Dev., 9, 2157–2169.

  • Parkin DM, Bray FI and Devesa SS . (2001). Eur. J. Cancer, 37, S4–S66.

  • Reed JC . (2001). Trends Mol. Med., 7, 314–319.

  • Rittner K, Benavente A, Bompard-Sorlet A, Heitz F, Divita G, Brasseur R and Jacobs E . (2002). Mol. Ther., 5, 104–114.

  • Rothbard JB, Garlington S, Lin Q, Kirschberg T, Kreider E, McGrane PL, Wender P and Khavari PA . (2000). Nat. Med., 11, 1253–1257.

  • Salvesen GS and Duckett CS . (2002). Nat. Rev. Mol. Cell. Biol., 3, 401–410.

  • Scheffner M, Werness BA, Huibregtse JM, Levine AJ and Howley PM . (1990). Cell, 63, 1129–1136.

  • Schneider-Gaedicke A and Schwarz E . (1986). EMBO J., 5, 2285–2292.

  • Sedman SA, Barbosa MS, Vass WC, Hubbert NL, Haas JA, Lowy DR and Schiller JT . (1991). J. Virol., 65, 4860–4866.

  • Smotkin D, Prokoph H and Wettstein FO . (1989). J. Virol., 63, 1441–1447.

  • Southern PJ and Berg P . (1982). J. Mol. Appl. Genet., 1, 327–341.

  • Thomas M and Banks L . (1998). Oncogene, 17, 2943–2954.

  • Thomas M and Banks L . (1999). Oncogene, 18, 7690–7700.

  • Venturini F, Braspenning J, Homann M, Gissmann L and Sczakiel G . (1999). Nucleic Acids Res., 27, 1585–1592.

  • von Knebel Doeberitz M, Oltersdorf T, Schwarz E and Gissmann L . (1988). Cancer Res., 48, 3780–3786.

  • Wells SI, Francis DA, Karpova AY, Dowhanick JJ, Benson JD and Howley PM . (2000). EMBO J., 19, 5762–5771.

  • Zur Hausen H . (2002). Nat. Rev. Cancer, 2, 342–350.

Download references

Acknowledgements

This article is dedicated to Harald zur Hausen on the occasion of his retirement as head of the German Cancer Research Center with gratitude and appreciation for 20 years of leadership. We thank A Ullmann for excellent technical assistance. We are grateful to R Agami for plasmids pSUPER and pSUPER-p53, and to H Zentgraf for antibody 18E7C. TR was a recipient of a stipend of the Fondation pour la Recherche Médicale and currently has a stipend of the Alexander von Humboldt-Stiftung. This work was supported by the Deutsche Krebshilfe (I0-I930-Ho 5; HS) and the Zentrum für Molekulare Medizin Köln (MS).

Author information

Author notes

  1. Karin Butz and Tutik Ristriani: Both these authors contributed equally to this work

Authors and Affiliations

  1. Angewandte Tumorvirologie, Deutsches Krebsforschungszentrum, Im Neuenheimer Feld 242, Heidelberg, D-69120, Germany

    Karin Butz, Tutik Ristriani, Claudia Denk & Felix Hoppe-Seyler

  2. Zentrum für Biochemie, Medizinische Fakultät, Universität Köln, Joseph-Stelzmann-Str. 52, Köln, 50931, Germany

    Arnd Hengstermann & Martin Scheffner

Authors
  1. Karin Butz
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Tutik Ristriani
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Arnd Hengstermann
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claudia Denk
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Martin Scheffner
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Felix Hoppe-Seyler
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Felix Hoppe-Seyler.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Butz, K., Ristriani, T., Hengstermann, A. et al. siRNA targeting of the viral E6 oncogene efficiently kills human papillomavirus-positive cancer cells. Oncogene 22, 5938–5945 (2003). https://doi.org/10.1038/sj.onc.1206894

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206894

Keywords

This article is cited by

Search

Advanced search

Quick links