Skip to main content
SpringerLink
Log in

Over-expression of Mcl-1 impairs the ability of ATRA to induce growth arrest and differentiation in acute promyelocytic leukemia cells

  • Original Paper
  • Published:
Apoptosis Aims and scope Submit manuscript

Abstract

Exposure of acute promyelocytic leukemia (APL) cells to all-trans retinoic acid (ATRA) increases levels of Mcl-1, however, the implication of ATRA-mediated expressions of Mcl-1 in these cells remains to be fully elucidated. This study found that exposure of NB4 and PL-21 cells to ATRA increased levels of Mcl-1 in association with phosphorylation of c-jun N-terminus kinases. Down-regulation of Mcl-1 by a small interfering (siRNA) or an inhibitor of JNK significantly potentiated the ability of ATRA to induce differentiation and apoptosis in these cells. On the other hand, the anti-leukemia effects of ATRA were blunted when Mcl-1 was forced expressed in NB4 and PL-21 cells as well as leukemia cells isolated from individuals with APL. Furthermore, down-regulation of Mcl-1 by an siRNA sensitized non-APL U937 and KG-1 leukemia cells to ATRA-mediated differentiation and apoptosis. Taken together, inhibition of Mcl-1 might be useful to potentiate the action of ATRA in APL as well as non-APL AML cells.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

References

  1. Grimwade D, Walker H, Harrison G et al (2001) The predictive value of hierarchical cytogenetic classification in older adults with acute myeloid leukemia (AML): analysis of 1065 patients entered into the United Kingdom Medical Research Council AML11 trial. Blood 98:1312–1320

    Article  CAS  PubMed  Google Scholar 

  2. Grignani F, De Matteis S, Nervi C et al (1998) Fusion proteins of the retinoic acid receptor-alpha recruit histone deacetylase in promyelocytic leukaemia. Nature 391:815–818

    Article  CAS  PubMed  Google Scholar 

  3. Kizaki M, Dawson MI, Heyman R et al (1996) Effects of novel retinoid X receptor-selective ligands on myeloid leukemia differentiation and proliferation in vitro. Blood 87:1977–1984

    CAS  PubMed  Google Scholar 

  4. Gombart AF, Koeffler HP (2002) Neutrophil specific granule deficiency and mutations in the gene encoding transcription factor C/EBPε. Curr Opin Hematol 9:36–42

    Article  PubMed  Google Scholar 

  5. Soignet SL, Maslak P, Wang ZG et al (1998) Complete remission after treatment of acute promyelocytic leukemia with arsenic trioxide. N Engl J Med 339:1341–1348

    Article  CAS  PubMed  Google Scholar 

  6. Wolf G, Smas CM (2000) Retinoic acid induces the degradation of the leukemogenic protein encoded by the promyelocytic leukemia gene fused to the retinoic acid receptor alpha gene. Nutr Rev 58:211–214

    Article  CAS  PubMed  Google Scholar 

  7. Kozopas KM, Yang T, Buchan HL, Zhou P, Craig RW (1993) MCL1, a gene expressed in programmed myeloid cell differentiation, has sequence similarity to bcl-2. Proc Natl Acad Sci USA 90:3516–3520

    Article  CAS  PubMed  Google Scholar 

  8. Yang T, Kozopas KM, Craig RW (1995) The intracellular distribution and pattern of expression of Mcl-1 overlap with, but are not identical to, those of Bcl-2. J Cell Biol 128:1173–1184

    Article  CAS  PubMed  Google Scholar 

  9. Opferman J, Iwasaki H, Ong CC et al (2005) Obligate role of anti-apoptotic MCL-1 in the survival of hematopoietic stem cells. Science 307:1101–1104

    Article  CAS  PubMed  Google Scholar 

  10. Campbell CJ, Lee JB, Levadoux-Martin M et al (2010) The human stem cell hierarchy is defined by a functional dependence on Mcl-1 for self-renewal capacity. Blood 116:1433–1442

    Article  CAS  PubMed  Google Scholar 

  11. Zhang B, Gojo I, Fenton RG (2002) Myeloid cell factor-1 is a critical survival factor for multiple myeloma. Blood 99:1885–1893

    Article  CAS  PubMed  Google Scholar 

  12. Kaufmann SH, Karp JE, Svingen PA et al (1998) Elevated expression of the apoptotic regulator Mcl-1 at the time of leukemic relapse. Blood 91:991–1000

    CAS  PubMed  Google Scholar 

  13. Stam RW, Den Boer ML, Schneider P et al (2010) Association of high-level MCL-1 expression with in vitro and in vivo prednisone resistance in MLL rearranged infant acute lymphoblastic leukemia. Blood 115:1018–1025

    Article  CAS  PubMed  Google Scholar 

  14. Pepper C, Lin TT, Pratt G et al (2008) Mcl-1 expression has in vitro and in vivo significance in chronic lymphocytic leukemia and is associated with other poor prognostic markers. Blood 112:3807–3817

    Article  CAS  PubMed  Google Scholar 

  15. Kitada S, Andersen J, Akar S et al (1998) Expression of apoptosis-regulating proteins in chronic lymphocytic leukemia: correlations with in vitro and in vivo chemoresponses. Blood 91:3379–3389

    CAS  PubMed  Google Scholar 

  16. Zhou P, Qian L, Bieszczad CK et al (1998) Mcl-1 in transgenic mice promotes survival in a spectrum of hematopoietic cell types and immortalization in the myeloid lineage. Blood 92:3226–3239

    CAS  PubMed  Google Scholar 

  17. Zhou P, Levy NB, Xie H et al (2001) MCL1 transgenic mice exhibit a high incidence of B-cell lymphoma manifested as a spectrum of histologic subtypes. Blood 97:3902–3909

    Article  CAS  PubMed  Google Scholar 

  18. Beroukhim R, Mermel C, Porter D et al (2010) The landscape of somatic copy-number alteration across human cancers. Nature 463:899–905

    Article  CAS  PubMed  Google Scholar 

  19. Xia L, Wurmbach E, Waxman S, Jing Y (2006) Upregulation of Bfl-1/A1 in leukemia cells undergoing differentiation by all-trans retinoic acid treatment attenuates chemotherapeutic agent-induced apoptosis. Leukemia 20:1009–1016

    Article  CAS  PubMed  Google Scholar 

  20. Gianni M, Peviani M, Bruck N et al (2012) p38αMAPK interacts with and inhibits RARα: suppression of the kinase enhances the therapeutic activity of retinoids in acute myeloid leukemia cells. Leukemia 26:1850–1861

    Article  CAS  PubMed  Google Scholar 

  21. Gazel A, Banno T, Walsh R, Blumenberg M (2006) Inhibition of JNK promotes differentiation of epidermal keratinocytes. J Biol Chem 281:20530–20541

    Article  CAS  PubMed  Google Scholar 

  22. Mendelson KG, Contois LR, Tevosian SG, Davis RJ, Paulson KE (1996) Independent regulation of JNK/p38 mitogen-activated protein kinases by metabolic oxidative stress in the liver. Proc Natl Acad Sci USA 93:12908–12913

    Article  CAS  PubMed  Google Scholar 

  23. Lee LF, Li G, Templeton DJ, Ting JP (1998) Paclitaxel (Taxol)-induced gene expression and cell death are both mediated by the activation of c-Jun NH2 terminal kinase (JNK/SAPK). J Biol Chem 273:28253–28260

    Article  CAS  PubMed  Google Scholar 

  24. Davis RJ (2000) Signal transduction by the JNK group of MAP kinases. Cell 103:239–252

    Article  CAS  PubMed  Google Scholar 

  25. Bubici C, Papa S, Pham CG, Zazzeroni F, Franzoso G (2004) NF-kB and JNK: an intricate affair. Cell Cycle 3:1524–1529

    Article  CAS  PubMed  Google Scholar 

  26. Sabapathy K, Wagner EF (2004) JNK2: a negative regulator of cellular proliferation. Cell Cycle 3:1520–1523

    Article  CAS  PubMed  Google Scholar 

  27. Nagata Y, Nishida E, Todokoro K (1997) Activation of JNK signaling pathway by erythropoietin, thrombopoietin, and interleukin-3. Blood 89:2664–2669

    CAS  PubMed  Google Scholar 

  28. Ikezoe T, Chen SS, Yang Y, Heber D, Taguchi H, Koeffler HP (2003) PC-SPES: Molecular mechanism to induce apoptosis and down-regulate expression of PSA in LNCaP human prostate cancer cells. Int J Oncol 23:1461–1470

    PubMed  Google Scholar 

  29. Yang Y, Ikezoe T, Saito T, Kobayashi M, Koeffler HP, Taguchi H (2004) Proteasome inhibitor PS-341 induces growth arrest and apoptosis of non-small cell lung cancer cells via the JNK/c-Jun/AP-1 signaling. Cancer Sci 95:176–180

    Article  CAS  PubMed  Google Scholar 

  30. Kodama Y, Taura K, Miura K, Schnabl B, Osawa Y, Brenner DA (2009) Antiapoptotic effect of c-Jun N-terminal kinase-1 through Mcl-1 stabilization in TNF-induced hepatocyte apoptosis. Gastroenterology 136:1423–1434

    Article  CAS  PubMed  Google Scholar 

  31. Kubonishi I, Machida K, Niiya K et al (1984) Establishment of a new peroxidase-positive human myeloid cell line, PL-21. Blood 63:254–259

    CAS  PubMed  Google Scholar 

  32. Nishioka C, Ikezoe T, Yang J, Gery S, Koeffler HP, Yokoyama A (2009) Inhibition of mammalian target of rapamycin signaling potentiates the effects of all-trans retinoic acid to induce growth arrest and differentiation of human acute myelogenous leukemia cells. Int J Cancer 125:1710–1720

    Article  CAS  PubMed  Google Scholar 

  33. Wergeland L, Sjøholt G, Haaland I, Hovland R, Bruserud Ø, Gjertsen BT (2007) Pre-apoptotic response to therapeutic DNA damage involves protein modulation of Mcl-1, Hdm2 and Flt3 in acute myeloid leukemia cells. Mol Cancer 6:33

    Article  PubMed  Google Scholar 

  34. Soucek K, Pacherník J, Kubala L, Vondrácek J, Hofmanová J, Kozubík A (2006) Transforming growth factor-beta1 inhibits all-trans retinoic acid-induced apoptosis. Leuk Res 30:607–623

    Article  CAS  PubMed  Google Scholar 

  35. Bedi R, Du J, Sharma AK, Gomes I, Ackerman SJ (2009) Human C/EBP-epsilon activator and repressor isoforms differentially reprogram myeloid lineage commitment and differentiation. Blood 113:317–327

    Article  CAS  PubMed  Google Scholar 

  36. Theilgaard-Mönch K, Jacobsen LC, Borup R et al (2005) The transcriptional program of terminal granulocytic differentiation. Blood 105:1785–1796

    Article  PubMed  Google Scholar 

  37. Barinaga M (1996) Life-death balance within the cell. Science 274:724

    Article  CAS  PubMed  Google Scholar 

  38. De Smaele E, Zazzeroni F, Papa S et al (2001) Induction of gadd45beta by NF-kappaB downregulates pro-apoptotic JNK signalling. Nature 414:308–313

    Article  PubMed  Google Scholar 

  39. Ventura JJ, Hubner A, Zhang C, Flavell RA, Shokat KM, Davis RJ (2006) Chemical genetic analysis of the time course of signal transduction by JNK. Mol Cell 21:701–710

    Article  CAS  PubMed  Google Scholar 

  40. Wang Q, Wieder R (2004) All-trans retinoic acid potentiates Taxotere-induced cell death mediated by Jun N-terminal kinase in breast cancer cells. Oncogene 23:426–433

    Article  CAS  PubMed  Google Scholar 

  41. Huang HS, Liu ZM, Hong DY (2010) Blockage of JNK pathway enhances arsenic trioxide-induced apoptosis in human keratinocytes. Toxicol Appl Pharmacol 244:234–241

    Article  CAS  PubMed  Google Scholar 

  42. Yu C, Minemoto Y, Zhang J et al (2004) JNK suppresses apoptosis via phosphorylation of the proapoptotic Bcl-2 family protein BAD. Mol Cell 13:329–340

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported in part by The Kochi University President’s Discretionary Grant (to T.I).

Conflict of interest

The authors have no conflict of interest to declare.

Author information

Authors and Affiliations

  1. Department of Hematology and Respiratory Medicine, Kochi Medical School, Kochi University, Nankoku, Kochi, 783-8505, Japan

    Jing Yang, Takayuki Ikezoe, Chie Nishioka & Akihito Yokoyama

Authors
  1. Jing Yang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Takayuki Ikezoe
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Chie Nishioka
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Akihito Yokoyama
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Takayuki Ikezoe.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Yang, J., Ikezoe, T., Nishioka, C. et al. Over-expression of Mcl-1 impairs the ability of ATRA to induce growth arrest and differentiation in acute promyelocytic leukemia cells. Apoptosis 18, 1403–1415 (2013). https://doi.org/10.1007/s10495-013-0872-0

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10495-013-0872-0

Keywords

Search

Navigation