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.

Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex

Abstract

Multiple myeloma (MM) is a rapidly fatal plasma-cell malignancy that evolves mainly in the bone marrow. Melphalan is widely used to treat patients with MM but as yet its mechanisms of action are poorly documented. In the current study, we demonstrate that melphalan induces a drastic downregulation of Mcl-1L, Bcl-xL and BimEL in human melphalan-sensitive myeloma cells while the most potent proapoptotic isoforms, BimL and S, are affected to a lesser extent. Moreover, Mcl-1L and BimEL disappearance is associated with the generation of proapoptotic cleaved forms generated by a caspase cleavage. In myeloma cells, we have previously shown that Mcl-1 neutralizes the proapoptotic function of Bim and therefore, prevents the activation of death effectors. In this study, we demonstrate that melphalan disrupts the Mcl-1/Bim complex whereas the Bcl-2/Bim complex is not modified. The disappearance of full length Mcl-1 allows the release of Bim isoforms, particularly L and S, which can exert their proapoptotic function and leads to Bax activation and cytochrome c release. Thus, we can hypothesize that the cleaved 26 kDa proapoptotic Mcl-1 and the 19 and 12 kDa of Bim, generated during melphalan treatment could contribute to the amplification loop of apoptosis.

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

Relevant articles

Open Access articles citing this article.

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1
Figure 2
Figure 3

Abbreviations

BH:

Bcl-2 homology (domain)

References

  • Bouillet P, Metcalf D, Huang DC, Tarlinton DM, Kay TW, Kontgen F, Adams JM and Strasser A . (1999). Science, 286, 1735–1738.

  • Chen D and Zhou Q . (2004). Proc. Natl. Acad. Sci. USA, 101, 1235–1240.

  • Clem RJ, Cheng EH, Karp CL, Kirsch DG, Ueno K, Takahashi A, Kastan MB, Griffin DE, Earnshaw WC, Velivona MA and Hardwick JM . (1998). Proc. Natl. Acad. Sci. USA, 95, 554–559.

  • Cory S, Huang DC and Adams JM . (2003). Oncogene, 22, 8590–8607.

  • Craig RW . (2002). Leukemia, 16, 444–454.

  • Degterev A, Lugovskoy A, Cardone M, Mulley B, Wagner G, Mitchison T and Yuan J . (2001). Nat. Cell Biol., 3, 173–182.

  • Derenne S, Monia B, Dean NM, Taylor JK, Rapp MJ, Harousseau JL, Bataille R and Amiot M . (2002). Blood, 100, 194–199.

  • Gomez-Bougie P, Bataille R and Amiot M . (2004). Eur. J. Immunol., 34, 3156–3164.

  • Gomez-Bougie P, Bataille R and Amiot M . (2005). Eur. J. Immunol., 35, 971–976.

  • Gross A, McDonnell JM and Korsmeyer SJ . (1999). Genes Dev., 13, 1899–1911.

  • Herrant M, Jacquel A, Marchetti S, Belhacene N, Colosetti P, Luciano F and Auberger P . (2004). Oncogene, 23, 7863–7873.

  • Huang DC and Strasser A . (2000). Cell, 103, 839–842.

  • Jourdan M, Veyrune JL, Vos JD, Redal N, Couderc G and Klein B . (2003). Oncogene, 22, 2950–2959.

  • Michels J, Johnson and Packham G . (2005). Int. J. Biochem. Cell Biol., 37, 267–271.

  • Michels J, O'Neill JW, Dallman CL, Mouzakiti A, Habens F, Brimmell M, Zhang KY, Craig RW, Marcusson EG, Johnson PW and Packham G . (2004). Oncogene, 23, 4818–4827.

  • Moreau P, Facon T, Attal M, Hulin C, Michallet M, Maloisel F, Sotto JJ, Guilhot F, Marit G, Doyen C, Jaubert J, Fuzibet JG, Francois S, Benboubker L, Monconduit M, Voillat L, Macro M, Berthou C, Dorvaux V, Pignon B, Rio B, Matthes T, Casassus P, Caillot D, Najman N, Grosbois B, Bataille R, Harousseau JL and Intergroupe Francophone du Myelome. (2002). Blood, 99, 731–735.

  • Morishima N, Nakanishi K, Takenouchi H, Shibata T and Yasuhiko Y . (2002). J. Biol. Chem., 277, 34287–34294.

  • O'Connor L, Strasser A, O'Reilly LA, Hausmann G, Adams JM, Cory S and Huang DC . (1998). EMBO J., 17, 384–395.

  • Oliver L, Priault M, Tremblais K, LeCabellec MT, Meflah K, Manon S and Vallette FM . (2000). FEBS Lett., 487, 161–165.

  • Opferman JT, Letai A, Beard C, Sorcinelli MD, Ong CC and Korsmeyer SJ . (2003). Nature, 426, 671–676.

  • Pei XY, Dai Y and Grant S . (2003). Leukemia, 10, 2036–2045.

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

  • Snowden RT, Sun XM, Dyer MJ and Cohen GM . (2003). Leukemia, 10, 1981–1989.

  • Tzung SP, Kim KM, Basanez G, Giedt CD, Simon J, Zimmerberg J, Zhang KY and Hockenbery DM . (2001). Nat. Cell Biol., 3, 183–191.

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

  • Zhang B, Gojo I and Fenton RG . (2002). Blood, 9, 1885–1893.

  • Zhu Y, Swanson BJ, Wang M, Hildeman DA, Schaefer BC, Liu X, Suzuki H, Mihara K, Kappler J and Marrack P . (2004). Proc. Natl. Acad. Sci. USA, 101, 7681–7686.

Download references

Acknowledgements

This work was supported by The Ligue Nationale contre le Cancer (équipe labelisée 2005).

Author information

Authors and Affiliations

Authors

Rights and permissions

Reprints and Permissions

About this article

Cite this article

Gomez-Bougie, P., Oliver, L., Le Gouill, S. et al. Melphalan-induced apoptosis in multiple myeloma cells is associated with a cleavage of Mcl-1 and Bim and a decrease in the Mcl-1/Bim complex. Oncogene 24, 8076–8079 (2005). https://doi.org/10.1038/sj.onc.1208949

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/sj.onc.1208949

Keywords

  • multiple myeloma
  • melphalan
  • Mcl-1
  • Bcl-2
  • BH3-only Bim

This article is cited by

Search

Quick links