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:

Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene

Oncogene volume 22, pages 8330–8336 (2003)Cite this article

Abstract

Increased resistance to apoptosis is a hallmark of many tumor cells. The functional inhibition of specific antiapoptotic factors may provide a rational basis for the development of novel therapeutic strategies. We investigated here whether the RNA interference (RNAi) technology could be used to increase the apoptotic susceptibility of cancer cells. As a molecular target, we chose the antiapoptotic livin (ML-IAP, KIAP) gene, which is expressed in a subset of human tumors. We identified vector-borne small interfering (si)RNAs, which could efficiently block endogenous livin gene expression. Silencing of livin was associated with caspase-3 activation and a strongly increased apoptotic rate in response to different proapoptotic stimuli, such as doxorubicin, UV-irradiation, or TNFα. The effects were specific for Livin-expressing tumor cells. Our results (i) provide direct evidence that the intracellular interference with livin gene expression resensitizes human tumor cells to apoptosis, (ii) define the livin gene as a promising molecular target for therapeutic inhibition, and (iii) show that the livin gene is susceptible to efficient and specific silencing by the siRNA technology.

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.

  • Ashhab Y, Alian A, Polliack A, Panet A and Yehuda DB . (2001). FEBS Lett., 495, 56–60.

  • Borkhardt A . (2002). Cancer Cell, 2, 167–168.

  • 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 and Hoppe-Seyler F . (1993). J. Virol., 67, 6476–6486.

  • Butz K, Whitaker N, Denk C, Ullmann A, Geisen C and Hoppe-Seyler F . (1999). Oncogene, 18, 2381–2386.

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

  • Deveraux QL and Reed JR . (1999). Genes Dev., 13, 239–252.

  • Du C, Fang M, Li Y and Wang X . (2000). Cell, 102, 33–42.

  • 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.

  • 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.

  • Gazzaniga P, Gradilone A, Guilani L, Gandini O, Silvestri I, Nofroni I, Saccani G, Frati L and Agliano AM . (2003). Ann. Oncol., 14, 85–90.

  • Green DR and Evan GI . (2002). Cancer Cell, 1, 19–30.

  • Hannon GJ . (2002). Nature, 418, 244–251.

  • Herr I and Debatin K-M . (2001). Blood, 98, 2603–2614.

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

  • Johnstone RW, Ruefi A and Lowe SW . (2002). Cell, 108, 153–164.

  • Kasof GM and Gomes BC . (2001). J. Biol. Chem., 276, 3238–3246.

  • LaCasse E, Baird S, Korneluk RG and MacKenzie AE . (1998). Oncogene, 17, 3247–3259.

  • Lewis DL, Hagstrom JE, Loomis AG, Wolff JA and Herweijer A . (2002). Nat. Genet., 32, 107–108.

  • Lin J-H, Deng G, Huang Q and Morser J . (2000). Biochim. Biophys. Res. Commun., 279, 820–831.

  • McCaffrey AP, Meuse L, Pham T-TT, Conklin DS, Hannon GJ and Kay MA . (2002). Nature, 418, 38–39.

  • McManus MT and Sharp PA . (2002). Nat. Rev. Genet., 3, 737–747.

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

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

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

  • Reed JC . (2003). Cancer Cell, 3, 17–22.

  • 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.

  • Rothbard JB, Kreider E, VanDeusen CL, Wright L, Wylie BL and Wender PA . (2002). J. Med. Chem., 45, 3612–3618.

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

  • Sanna MG, da Silva Correia J, Ducrey O, Lee J, Nomoto K, Schrantz N, Deveraux QL and Ulevitch RJ . (2002). Mol. Cell. Biol., 22, 1754–1766.

  • Slee EA, Adrain C and Martin SJ . (1999). Cell Death Differ., 6, 1067–1074.

  • Song E, Lee S-K, Wang J, Ince N, Ouyang N, Min J, Chen J, Shankar P and Lieberman J . (2003). Nat. Med., 10, 2002 Published Online February, 10.1038/nm828.

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

  • Stennicke HR, Deveraux QL, Humke EW, Reed JC, Dixit VM and Salvesen GS . (1999). J. Biol. Chem., 274, 8359–8362.

  • Tuschl T . (2002). Nat. Biotechnol., 20, 446–448.

  • Verhagen AM, Ekert PG, Pakusch M, Silke J, Conolly LM, Reid GE, Moritz RL, Simpson RJ and Vaux DL . (2000). Cell, 102, 43–53.

  • Verhagen AM and Vaux DL . (2002). Apoptosis, 7, 163–166.

  • Vucic D, Deshayes K, Ackerley H, Pisabarro MT, Kadkhodayan S, Fairbrother WJ and Dixit VM . (2002). J. Biol. Chem., 277, 12275–12279.

  • Vucic D, Stennicke HR, Pisabarro MT, Salvesen GS and Dixit VM . (2000). Curr. Biol., 10, 1359–1366.

  • Wilde M, Fuchs U, Wössmann W and Borkhardt A . (2002). Oncogene, 21, 5716–5724.

  • Xia H, Mao Q, Paulsen HL and Davidson BL . (2002). Nat. Biotechnol., 20, 1006–1010.

Download references

Acknowledgements

We thank Julia Semzow for excellent technical assistance, Dr Reuven Agami for the pSUPER plasmid, Dr Yakoub Ashhab for the livin cDNA probe, and Dr Simone Fulda for antibodies. This work was supported by a grant from the Wilhelm-Sander-Stiftung to KB (2001.052.1).

Author information

Authors and Affiliations

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

    Irena Crnkovic-Mertens, Felix Hoppe-Seyler & Karin Butz

Authors
  1. Irena Crnkovic-Mertens
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Felix Hoppe-Seyler
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Karin Butz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Karin Butz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Crnkovic-Mertens, I., Hoppe-Seyler, F. & Butz, K. Induction of apoptosis in tumor cells by siRNA-mediated silencing of the livin/ML-IAP/KIAP gene. Oncogene 22, 8330–8336 (2003). https://doi.org/10.1038/sj.onc.1206973

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1206973

Keywords

This article is cited by

Search

Advanced search

Quick links