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:

TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway

Oncogene volume 24, pages 4052–4064 (2005)Cite this article

Abstract

The death ligand TRAIL has been suggested as a suitable biological agent for the selective induction of cell death in cancer cells. Moreover, TRAIL synergizes with DNA-damaging therapies such as chemotherapeutic drugs or ionizing irradiation (IR). Here, we show that synergy of TRAIL and IR, that is, crosssensitization between TRAIL and IR for induction of apoptosis, entirely depends on Bax proficiency in human DU145 and HCT116 carcinoma cells. DU145 prostate carcinoma cells that have lost Bax protein expression due to mutation fail to activate caspase-3 and -9 when exposed to TRAIL and IR. In contrast, TRAIL sensitized for IR-induced apoptosis and vice versa upon reconstitution of Bax expression. Notably, both DU145 and HCT116 still express significant levels of the multidomain proapoptotic Bcl-2 homolog Bak. This indicates that Bak is not sufficient to mediate crosssensitization and synergism between IR and TRAIL. These data clearly establish distinct roles for Bax and Bak in linking the TRAIL death receptor pathway to the mitochondrial apoptosis signaling cascade upon DNA damage by IR.

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
Figure 6
Figure 7
Figure 8
Figure 9

Similar content being viewed by others

References

  • Ashkenazi A, Pai RC, Fong S, Leung S, Lawrence DA, Marsters SA, Blackie C, Chang L, McMurtrey AE, Hebert A, DeForge L, Koumenis IL, Lewis D, Harris L, Bussiere J, Koeppen H, Shahrokh Z and Schwall RH . (1999). J. Clin. Invest., 104, 155–162.

  • Ballestrero A, Nencioni A, Boy D, Rocco I, Garuti A, Mela GS, Van Parijs L, Brossart P, Wesselborg S and Patrone F . (2004). Clin. Cancer Res., 10, 1463–1470.

  • Belka C, Rudner J, Wesselborg S, Stepczynska A, Marini P, Lepple-Wienhues A, Faltin H, Bamberg M, Budach W and Schulze-Osthoff K . (2000). Oncogene, 19, 1181–1190.

  • Belka C, Schmid B, Marini P, Durand E, Rudner J, Faltin H, Bamberg M, Schulze-Osthoff K and Budach W . (2001). Oncogene, 20, 2190–2196.

  • Bonavida B, Ng CP, Jazirehi A, Schiller G and Mizutani Y . (1999). Int. J. Oncol., 15, 793–802.

  • Bosanquet AG, Sturm I, Wieder T, Essmann F, Bosanquet MI, Head DJ, Dörken B and Daniel PT . (2002). Leukemia, 16, 1035–1044.

  • Bunz F, Hwang PM, Torrance C, Waldman T, Zhang Y, Dillehay L, Williams J, Lengauer C, Kinzler KW and Vogelstein B . (1999). J. Clin. Invest., 104, 263–269.

  • Cartron P-F, Juin P, Oliver L, Martin S, Meflah K and Vallette FM . (2003). Mol. Cell. Biol., 23, 4701–4712.

  • Cheng EH, Sheiko TV, Fisher JK, Craigen WJ and Korsmeyer SJ . (2003). Science, 301, 513–517.

  • Cheng EH, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T and Korsmeyer SJ . (2001). Mol. Cell, 8, 705–711.

  • Coney LR, Daniel PT, Sanborn D, Dhein J, Debatin KM, Krammer PH and Zurawski Jr VR . (1994). Int. J. Cancer, 58, 562–567.

  • Daniel PT, Schulze-Osthoff K, Belka C and Güner D . (2003). Essays Biochem., 39, 73–88.

  • Daniel PT, Sturm I, Wieder T and Schulze-Osthoff K . (2001). Leukemia, 15, 1022–1032.

  • Deng Y, Lin Y and Wu X . (2002). Genes Dev., 16, 33–45.

  • Dhein J, Daniel PT, Trauth BC, Oehm A, Moller P and Krammer PH . (1992). J. Immunol., 149, 3166–3173.

  • Eberle J, Fecker LF, Hossini AM, Wieder T, Daniel PT, Orfanos CE and Geilen CC . (2003). Oncogene, 22, 9131–9141.

  • Engels IH, Stepczynska A, Stroh C, Lauber K, Berg C, Schwenzer R, Wajant H, Janicke RU, Porter AG, Belka C, Gregor M, Schulze-Osthoff K and Wesselborg S . (2000). Oncogene, 19, 4563–4573.

  • Eskes R, Desagher S, Antonsson B and Martinou JC . (2000). Mol. Cell. Biol., 20, 929–935.

  • Essmann F, Wieder T, Otto A, Muller EC, Dörken B and Daniel PT . (2000). Biochem. J., 346, 777–783.

  • Friedrich K, Wieder T, von Haefen C, Radetzki S, Jänicke R, Schulze-Osthoff K, Dörken B and Daniel PT . (2001). Oncogene, 20, 2749–2760.

  • Fulda S, Meyer E and Debatin KM . (2002). Oncogene, 21, 2283–2294.

  • Gillissen B, Essmann F, Graupner V, Stärck L, Radetzki S, Dörken B, Schulze-Osthoff K and Daniel PT . (2003). EMBO J., 22, 3580–3590.

  • Gliniak B and Le T . (1999). Cancer Res., 59, 6153–6158.

  • Güner D, Sturm I, Hemmati PG, Hermann S, Hauptmann S, Wurm R, Budach V, Dörken B, Lorenz M and Daniel PT . (2002). Int. J. Cancer, 103, 445–454.

  • Hasenjäger A, Gillissen B, Müller A, Normand G, Hemmati PG, Schuler M, Dörken B and Daniel PT . (2004). Oncogene, 23, 4523–4535.

  • Hemmati PG, Gillissen B, von Haefen C, Wendt J, Stärck L, Güner D, Dörken B and Daniel PT . (2002). Oncogene, 21, 3149–3161.

  • Klöpfer A, Hasenjäger A, Belka C, Schulze-Osthoff K, Dörken B and Daniel PT . (2004). Oncogene, 23, 9408–9418.

  • Korsmeyer SJ, Wei MC, Saito M, Weiler S, Oh KJ and Schlesinger PH . (2000). Cell Death Differ., 7, 1166–1173.

  • LeBlanc H, Lawrence D, Varfolomeev E, Totpal K, Morlan J, Schow P, Fong S, Schwall R, Sinicropi D and Ashkenazi A . (2002). Nat. Med., 8, 274–281.

  • Lucking-Famira KM, Daniel PT, Moller P, Krammer PH and Debatin KM . (1994). Leukemia, 8, 1825–1833.

  • Luo X, Budihardjo I, Zou H, Slaughter C and Wang X . (1998). Cell, 94, 481–490.

  • Marini P, Jendrossek V, Durand E, Gruber C, Budach W and Belka C . (2003). Radiother. Oncol., 68, 189–198.

  • Martinou JC and Green DR . (2001). Nat. Rev. Mol. Cell Biol., 2, 63–67.

  • Mrozek A, Petrowsky H, Sturm I, Krauss J, Hermann S, Hauptmann S, Lorenz M and Daniel P . (2002). Cell Death Differ., 10, 461–467.

  • Newton K and Strasser A . (2000). J. Exp. Med., 191, 195–200.

  • Prokop A, Wieder T, Sturm I, Essmann F, Seeger K, Wuchter C, Ludwig W-D, Henze G, Dörken B and Daniel PT . (2000). Leukemia, 14, 1606–1613.

  • Prokop A, Wrasidlo W, Lode H, Herold R, Lang F, Henze G, Dörken B, Wieder T and Daniel PT . (2003). Oncogene, 22, 9107–9120.

  • Radetzki S, Köhne CH, von Haefen C, Gillissen B, Sturm I, Dörken B and Daniel PT . (2002). Oncogene, 21, 227–238.

  • Raisova M, Bektas M, Wieder T, Daniel P, Eberle J, Orfanos CE and Geilen CC . (2000). FEBS Lett., 473, 27–32.

  • Raisova M, Hossini A, Eberle J, Riebeling C, Wieder T, Sturm I, Daniel PT, Orfanos CE and Geilen CC . (2001). J. Invest. Dermatol., 177, 333–340.

  • Rudner J, Jendrossek V, Lauber K, Daniel PT, Wesselborg S and Belka C . (2005). Oncogene, 24, 130–140.

  • Schelwies K, Sturm I, Grabowski P, Scherübl H, Schindler I, Hermann S, Stein H, Buhr HJ, Riecken EO, Zeitz M, Dörken B and Daniel PT . (2002). Int. J. Cancer, 99, 589–596.

  • Schmelz K, Wieder T, Tamm I, Müller A, Essmann F, Geilen CC, Schulze-Osthoff K, Dörken B and Daniel PT . (2004). Oncogene, 23, 6743–6759.

  • Slee EA, Keogh SA and Martin SJ . (2000). Cell Death Differ., 7, 556–565.

  • Sturm I, Bosanquet A, Hermann S, Güner D, Dörken B and Daniel P . (2002). Cell Death Differ., 10, 477–484.

  • Sturm I, Kohne CH, Wolff G, Petrowsky H, Hillebrand T, Hauptmann S, Lorenz M, Dörken B and Daniel PT . (1999). J. Clin. Oncol., 17, 1364–1374.

  • Sturm I, Papadopoulos S, Hillebrand T, Benter T, Lück H-J, Wolff G, Dörken B and Daniel PT . (2000). Int. J. Cancer, 87, 517–521.

  • Sturm I, Petrowsky H, Volz R, Lorenz M, Radetzki S, Hillebrand T, Wolff G, Hauptmann S, Dörken B and Daniel PT . (2001). J. Clin. Oncol., 19, 2272–2281.

  • van Loo G, Saelens X, van Gurp M, MacFarlane M, Martin SJ and Vandenabeele P . (2002). Cell Death Differ., 9, 1031–1042.

  • von Haefen C, Gillissen B, Hemmati PG, Wendt J, Güner D, Mrozek A, Belka C, Dörken B and Daniel PT . (2004). Oncogene, 23, 8320–8332.

  • von Haefen C, Wieder T, Essmann F, Schulze-Osthoff K, Dörken B and Daniel PT . (2003). Oncogene, 22, 2236–2247.

  • von Haefen C, Wieder T, Gillissen B, Stärck L, Graupner V, Dörken B and Daniel PT . (2002). Oncogene, 21, 4009–4019.

  • Walczak H, Bouchon A, Stahl H and Krammer PH . (2000). Cancer Res., 60, 3051–3057.

  • Walczak H, Miller RE, Ariail K, Gliniak B, Griffith TS, Kubin M, Chin W, Jones J, Woodward A, Le T, Smith C, Smolak P, Goodwin RG, Rauch CT, Schuh JC and Lynch DH . (1999). Nat. Med., 5, 157–163.

  • Waldman T, Lengauer C, Kinzler KW and Vogelstein B . (1996). Nature, 381, 713–716.

  • Wei MC, Zong WX, Cheng EH, Lindsten T, Panoutsakopoulou V, Ross AJ, Roth KA, MacGregor GR, Thompson CB and Korsmeyer SJ . (2001). Science, 292, 727–730.

  • Wen J, Ramadevi N, Nguyen D, Perkins C, Worthington E and Bhalla K . (2000). Blood, 96, 3900–3906.

  • Wesselborg S, Engels IH, Rossmann E, Los M and Schulze-Osthoff K . (1999). Blood, 93, 3053–3063.

  • Wieder T, Essmann F, Prokop A, Schmelz K, Schulze-Osthoff K, Beyaert R, Dörken B and Daniel PT . (2001). Blood, 97, 1378–1387.

  • Wu G, Chai J, Suber TL, Wu JW, Du C, Wang X and Shi Y . (2000). Nature, 408, 1008–1012.

  • Yu J, Wang Z, Kinzler KW, Vogelstein B and Zhang L . (2003). Proc. Natl. Acad. Sci. USA, 100, 1931–1936.

  • Zhang L, Yu J, Park BH, Kinzler KW and Vogelstein B . (2000). Science, 290, 989–992.

Download references

Acknowledgements

Bax wild-type and Bax k.o. HCT116 cells were kindly provided by Dr Bert Vogelstein, Johns Hopkins University, Baltimore, USA. We thank Dr Klaus Schulze-Osthoff for supplying us with antibodies against caspase-8. This work was supported by the Deutsche Krebshilfe e.V., the Deutsche Forschungsgemeinschaft, and the Deutsche José Carreras Leukämiestiftung e.V.

Author information

Authors and Affiliations

  1. Department of Hematology, Oncology and Tumor Immunology, University Medical Center Charité, Humboldt University, Berlin, Germany

    Jana Wendt, Clarissa von Haefen, Philipp Hemmati, Bernd Dörken & Peter T Daniel

  2. Max Delbrück Center for Molecular Medicine, Berlin, Germany

    Philipp Hemmati, Bernd Dörken & Peter T Daniel

  3. Department of Radiation Oncology, Medical Faculty, Eberhard-Karls University, Tübingen, Germany

    Claus Belka

Authors
  1. Jana Wendt
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Clarissa von Haefen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Philipp Hemmati
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Claus Belka
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Bernd Dörken
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Peter T Daniel
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Peter T Daniel.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Wendt, J., von Haefen, C., Hemmati, P. et al. TRAIL sensitizes for ionizing irradiation-induced apoptosis through an entirely Bax-dependent mitochondrial cell death pathway. Oncogene 24, 4052–4064 (2005). https://doi.org/10.1038/sj.onc.1208580

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208580

Keywords

This article is cited by

Search

Advanced search

Quick links