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 Article
  • Published:

Apoptosis

Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells

Leukemia volume 22, pages 819–825 (2008)Cite this article

Abstract

Mcl-1 is an antiapoptotic Bcl-2 family member, whose degradation is supposedly required for the induction of apoptosis. However, histone deacetylase inhibitors (HDACi) induce apoptosis primarily through the Bak/Mcl-1/Noxa and Bim pathways without decreasing Mcl-1. To investigate this discrepancy, we examined the role of Mcl-1 on HDACi-mediated apoptosis. Inhibition of either class I or class II HDAC by selective HDACi caused an upregulation of Mcl-1 mRNA and protein. Downregulation of Mcl-1 by three structurally unrelated cyclin-dependent kinase inhibitors potentiated HDACi-mediated apoptosis in primary chronic lymphocytic leukemic (CLL) cells and K562 cells. Sensitivity to HDACi-induced apoptosis was increased ∼10-fold by the cyclin-dependent kinase inhibitors. Nanomolar concentrations of HDACi, ∼300-fold lower than that required to induce apoptosis alone, sensitized cells to TRAIL, emphasizing that the mechanism(s) whereby HDACi induce apoptosis is clearly distinct from those by which they sensitize to TRAIL. Furthermore, knockdown of Mcl-1-potentiated HDACi-mediated apoptosis in K562 cells. Thus, HDACi-mediated Mcl-1 upregulation plays an important antiapoptotic regulatory role in limiting the efficacy of HDACi-induced apoptosis, which can be overcome by combination with an agent that downregulates Mcl-1. Thus, a clinical trial in some cancers is warranted using a combination of an HDACi with agents that downregulate Mcl-1.

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 4
Figure 1
Figure 2
Figure 3

Similar content being viewed by others

References

  1. Danial NN, Korsmeyer SJ . Cell death: critical control points. Cell 2004; 116: 205–219.

    Article  CAS  PubMed  Google Scholar 

  2. Adams JM, Cory S . The Bcl-2 apoptotic switch in cancer development and therapy. Oncogene 2007; 26: 1324–1337.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Huang DC, Strasser A . BH3-only proteins-essential initiators of apoptotic cell death. Cell 2000; 103: 839–842.

    Article  CAS  PubMed  Google Scholar 

  4. Labi V, Erlacher M, Kiessling S, Villunger A . BH3-only proteins in cell death initiation, malignant disease and anticancer therapy. Cell Death Differ 2006; 13: 1325–1338.

    Article  CAS  PubMed  Google Scholar 

  5. Kitada S, Andersen J, Akar S, Zapata JM, Takayama S, Krajewski S et al. Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 1998; 91: 3379–3389.

    CAS  PubMed  Google Scholar 

  6. Pedersen IM, Kitada S, Leoni LM, Zapata JM, Karras JG, Tsukada N et al. Protection of CLL B cells by a follicular dendritic cell line is dependent on induction of Mcl-1. Blood 2002; 100: 1795–1801.

    Article  CAS  PubMed  Google Scholar 

  7. Petlickovski A, Laurenti L, Li X, Marietti S, Chiusolo P, Sica S et al. Sustained signaling through the B-cell receptor induces Mcl-1 and promotes survival of chronic lymphocytic leukemia B cells. Blood 2005; 105: 4820–4827.

    Article  CAS  PubMed  Google Scholar 

  8. Craig RW . MCL1 provides a window on the role of the BCL2 family in cell proliferation, differentiation and tumorigenesis. Leukemia 2002; 16: 444–454.

    Article  CAS  PubMed  Google Scholar 

  9. Michels J, Johnson PW, Packham G . Mcl-1. Int J Biochem Cell Biol 2005; 37: 267–271.

    Article  CAS  PubMed  Google Scholar 

  10. Opferman JT, Iwasaki H, Ong CC, Suh H, Mizuno S, Akashi K et al. Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 2005; 307: 1101–1104.

    Article  CAS  PubMed  Google Scholar 

  11. Fritsch RM, Schneider G, Saur D, Scheibel M, Schmid RM . Translational repression of MCL-1 couples stress-induced eIF2 alpha phosphorylation to mitochondrial apoptosis initiation. J Biol Chem 2007; 282: 22551–22562.

    Article  CAS  PubMed  Google Scholar 

  12. Rosato RR, Almenara JA, Kolla SS, Maggio SC, Coe S, Gimenez MS et al. Mechanism and functional role of XIAP and Mcl-1 down-regulation in flavopiridol/vorinostat antileukemic interactions. Mol Cancer Ther 2007; 6: 692–702.

    Article  CAS  PubMed  Google Scholar 

  13. Wang JM, Chao JR, Chen W, Kuo ML, Yen JJ, Yang-Yen HF . The antiapoptotic gene mcl-1 is up-regulated by the phosphatidylinositol 3-kinase/Akt signaling pathway through a transcription factor complex containing CREB. Mol Cell Biol 1999; 19: 6195–6206.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Inoshita S, Takeda K, Hatai T, Terada Y, Sano M, Hata J et al. Phosphorylation and inactivation of myeloid cell leukemia 1 by JNK in response to oxidative stress. J Biol Chem 2002; 277: 43730–43734.

    Article  CAS  PubMed  Google Scholar 

  15. Maurer U, Charvet C, Wagman AS, Dejardin E, Green DR . Glycogen synthase kinase-3 regulates mitochondrial outer membrane permeabilization and apoptosis by destabilization of MCL-1. Mol Cell 2006; 21: 749–760.

    Article  CAS  PubMed  Google Scholar 

  16. Mandelin II AM, Pope RM . Myeloid cell leukemia-1 as a therapeutic target. Expert Opin Ther Targets 2007; 11: 363–373.

    Article  CAS  PubMed  Google Scholar 

  17. Nijhawan D, Fang M, Traer E, Zhong Q, Gao W, Du F et al. Elimination of Mcl-1 is required for the initiation of apoptosis following ultraviolet irradiation. Genes Dev 2003; 17: 1475–1486.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Snowden RT, Sun XM, Dyer MJ, Cohen GM . Bisindolylmaleimide IX is a potent inducer of apoptosis in chronic lymphocytic leukaemic cells and activates cleavage of Mcl-1. Leukemia 2003; 17: 1981–1989.

    Article  CAS  PubMed  Google Scholar 

  19. Adams KW, Cooper GM . Rapid turnover of mcl-1 couples translation to cell survival and apoptosis. J Biol Chem 2007; 282: 6192–6200.

    Article  CAS  PubMed  Google Scholar 

  20. Cuconati A, Mukherjee C, Perez D, White E . DNA damage response and MCL-1 destruction initiate apoptosis in adenovirus-infected cells. Genes Dev 2003; 17: 2922–2932.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Willis SN, Chen L, Dewson G, Wei A, Naik E, Fletcher JI et al. Proapoptotic Bak is sequestered by Mcl-1 and Bcl-xL, but not Bcl-2, until displaced by BH3-only proteins. Genes Dev 2005; 19: 1294–1305.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Marks PA, Richon VM, Miller T, Kelly WK . Histone deacetylase inhibitors. Adv Cancer Res 2004; 91: 137–168.

    Article  CAS  PubMed  Google Scholar 

  23. Rosato RR, Grant S . Histone deacetylase inhibitors: insights into mechanisms of lethality. Expert Opin Ther Targets 2005; 9: 809–824.

    Article  CAS  PubMed  Google Scholar 

  24. Zhang Y, Adachi M, Kawamura R, Imai K . Bmf is a possible mediator in histone deacetylase inhibitors FK228 and CBHA-induced apoptosis. Cell Death Differ 2006; 13: 129–140.

    Article  CAS  PubMed  Google Scholar 

  25. Zhao Y, Tan J, Zhuang L, Jiang X, Liu ET, Yu Q . Inhibitors of histone deacetylases target the Rb-E2F1 pathway for apoptosis induction through activation of proapoptotic protein Bim. Proc Natl Acad Sci USA 2005; 102: 16090–16095.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Inoue S, Riley J, Gant TW, Dyer MJ, Cohen GM . Apoptosis induced by histone deacetylase inhibitors in leukemic cells is mediated by Bim and Noxa. Leukemia 2007; 21: 1773–1782.

    Article  CAS  PubMed  Google Scholar 

  27. Inoue S, MacFarlane M, Harper N, Wheat LM, Dyer MJ, Cohen GM . Histone deacetylase inhibitors potentiate TNF-related apoptosis-inducing ligand (TRAIL)-induced apoptosis in lymphoid malignancies. Cell Death Differ 2004; 11: S193–S206.

    Article  CAS  PubMed  Google Scholar 

  28. Inoue S, Mai A, Dyer MJ, Cohen GM . Inhibition of histone deacetylase class I but not class II is critical for the sensitization of leukemic cells to tumor necrosis factor-related apoptosis-inducing ligand-induced apoptosis. Cancer Res 2006; 66: 6785–6792.

    Article  CAS  PubMed  Google Scholar 

  29. Brown GR, Bamford AM, Bowyer J, James DS, Rankine N, Tang E et al. Naphthyl ketones: a new class of Janus kinase 3 inhibitors. Bioorg Med Chem Lett 2000; 10: 575–579.

    Article  CAS  PubMed  Google Scholar 

  30. Coll-Mulet L, Iglesias-Serret D, Santidrian AF, Cosialls AM, de Frias M, Castano E et al. MDM2 antagonists activate p53 and synergize with genotoxic drugs in B-cell chronic lymphocytic leukemia cells. Blood 2006; 107: 4109–4114.

    Article  CAS  PubMed  Google Scholar 

  31. Michels J, O'Neill JW, Dallman CL, Mouzakiti A, Habens F, Brimmell M et al. Mcl-1 is required for Akata6 B-lymphoma cell survival and is converted to a cell death molecule by efficient caspase-mediated cleavage. Oncogene 2004; 23: 4818–4827.

    Article  CAS  PubMed  Google Scholar 

  32. Qian DZ, Kato Y, Shabbeer S, Wei Y, Verheul HM, Salumbides B et al. Targeting tumor angiogenesis with histone deacetylase inhibitors: the hydroxamic acid derivative LBH589. Clin Cancer Res 2006; 12: 634–642.

    Article  CAS  PubMed  Google Scholar 

  33. Kawaguchi Y, Kovacs JJ, McLaurin A, Vance JM, Ito A, Yao TP . The deacetylase HDAC6 regulates aggresome formation and cell viability in response to misfolded protein stress. Cell 2003; 115: 727–738.

    Article  CAS  PubMed  Google Scholar 

  34. Chen R, Keating MJ, Gandhi V, Plunkett W . Transcription inhibition by flavopiridol: mechanism of chronic lymphocytic leukemia cell death. Blood 2005; 106: 2513–2519.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Kitada S, Zapata JM, Andreeff M, Reed JC . Protein kinase inhibitors flavopiridol and 7-hydroxy-staurosporine down-regulate antiapoptosis proteins in B-cell chronic lymphocytic leukemia. Blood 2000; 96: 393–397.

    CAS  PubMed  Google Scholar 

  36. Strasser A, Puthalakath H . Fold up or perish: unfolded protein response and chemotherapy. Cell Death Differ 2008; 15: 223–225.

    Article  CAS  PubMed  Google Scholar 

  37. Czabotar PE, Lee EF, van Delft MF, Day CL, Smith BJ, Huang DC et al. Structural insights into the degradation of Mcl-1 induced by BH3 domains. Proc Natl Acad Sci USA 2007; 104: 6217–6222.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Zhong Q, Gao W, Du F, Wang X . Mule/ARF-BP1, a BH3-only E3 ubiquitin ligase, catalyzes the polyubiquitination of Mcl-1 and regulates apoptosis. Cell 2005; 121: 1085–1095.

    Article  CAS  PubMed  Google Scholar 

  39. Dai Y, Grant S . Targeting multiple arms of the apoptotic regulatory machinery. Cancer Res 2007; 67: 2908–2911.

    Article  CAS  PubMed  Google Scholar 

  40. van Delft MF, Wei AH, Mason KD, Vandenberg CJ, Chen L, Czabotar PE et al. The BH3 mimetic ABT-737 targets selective Bcl-2 proteins and efficiently induces apoptosis via Bak/Bax if Mcl-1 is neutralized. Cancer Cell 2006; 10: 389–399.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Shapiro GI . Cyclin-dependent kinase pathways as targets for cancer treatment. J Clin Oncol 2006; 24: 1770–1783.

    Article  CAS  PubMed  Google Scholar 

  42. Han J, Goldstein LA, Gastman BR, Rabinowich H . Interrelated roles for Mcl-1 and BIM in regulation of TRAIL-mediated mitochondrial apoptosis. J Biol Chem 2006; 281: 10153–10163.

    Article  CAS  PubMed  Google Scholar 

  43. Ricci MS, Kim SH, Ogi K, Plastaras JP, Ling J, Wang W et al. Reduction of TRAIL-induced Mcl-1 and cIAP2 by c-Myc or sorafenib sensitizes resistant human cancer cells to TRAIL-induced death. Cancer Cell 2007; 12: 66–80.

    Article  CAS  PubMed  Google Scholar 

  44. Taniai M, Grambihler A, Higuchi H, Werneburg N, Bronk SF, Farrugia DJ et al. Mcl-1 mediates tumor necrosis factor-related apoptosis-inducing ligand resistance in human cholangiocarcinoma cells. Cancer Res 2004; 64: 3517–3524.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank Ms Joan Riley and Dr Shu Dong Zhang for validation of the primers for the real-time reverse transcription-PCR and statistical analysis, respectively. We thank Mr Roger Snowden for sharing data. This work was supported primarily by the UK Medical Research Council and some support from the Leukemia Research Fund.

Author information

Authors and Affiliations

  1. MRC Toxicology Unit, University of Leicester, Leicester, UK

    S Inoue, R Walewska, M J S Dyer & G M Cohen

Authors
  1. S Inoue
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. R Walewska
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. M J S Dyer
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. G M Cohen
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to G M Cohen.

Additional information

Supplementary Information accompanies the paper on the Leukemia website (http://www.nature.com/leu)

Supplementary information

Rights and permissions

Reprints and permissions

About this article

Cite this article

Inoue, S., Walewska, R., Dyer, M. et al. Downregulation of Mcl-1 potentiates HDACi-mediated apoptosis in leukemic cells. Leukemia 22, 819–825 (2008). https://doi.org/10.1038/leu.2008.1

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/leu.2008.1

Keywords

This article is cited by

Search

Advanced search

Quick links