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Medical Oncology

, 32:239 | Cite as

TRAF6 is required for BLyS-mediated NF-κB signaling in multiple myeloma cells

  • Xinfeng Wang
  • Jingjing Wang
  • Hong Liu
  • Ruirong Xu
  • Runsheng Ding
  • Shenhua Jiang
  • Xudong WangEmail author
  • Hongming HuangEmail author
Original Paper

Abstract

Tumor necrosis factor receptor-associated factor 6 (TRAF6) transduces signals from members of the IL-1R/TLR and TNFR superfamilies to the transcription factors NF-κB and AP1. Elevated expression of the TNF family member B-lymphocyte stimulator (BLyS) in multiple myeloma (MM) has been described recently. However, the precise process by which BLyS signals in myeloma cell remains unknown. Here, we identified increased expression of TRAF6 in MM patient cells and the MM cell lines U266, RPMI8226, and KM3. Furthermore, rhBLyS induced TRAF6 up-regulation in these cells in a dose-dependent manner. Both the classical and alternative NF-κB pathways were activated by rhBLyS treatment. Depletion of TRAF6 by siRNA decreased levels of p-p65 and p-p100, even after stimulation with rhBLyS. Down-regulation of TRAF6 also abrogated rhBLyS-mediated cell viability. These findings suggest that TRAF6 is required for BLyS-mediated NF-κB signaling in myeloma cells and is a potential molecular therapeutic target in MM.

Keywords

TRAF6 BLyS BAFF NF-κB Multiple myeloma 

Notes

Acknowledgments

Thanks for technical help from Ju Shaoqing, Ph.D., of Surgical Comprehensive Laboratory, Affiliated Hospital of Nantong University.

Funding source

This work was supported by the National Youth Science Foundation (81201857) and the Natural Science Foundation of Jiangsu Province, China (BK2011388).

Compliance with ethical standards

Conflict of interest

All the authors do not have any conflict of interest to declare.

References

  1. 1.
    Demchenko YN, Kuehl WM. A critical role for the NFkB pathway in multiple myeloma. Oncotarget. 2010;1:59–68.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Sanda T, Iida S, Ogura H, Asamitsu K, Murata T, Bacon KB, et al. Growth inhibition of multiple myeloma cells by a novel IkappaB kinase inhibitor. Clin Cancer Res. 2005;11:1974–82.CrossRefPubMedGoogle Scholar
  3. 3.
    Chung JY, Park YC, Ye H, Wu H. All TRAFs are not created equal: common and distinct molecular mechanisms of TRAF-mediated signal transduction. J Cell Sci. 2002;115:679–88.PubMedGoogle Scholar
  4. 4.
    Ben-David D, Livne E, Reznick AZ. The involvement of oxidants and NF-kappaB in cytokine-induced MMP-9 synthesis by bone marrow-derived osteoprogenitor cells. Inflamm Res. 2012;61:673–88.CrossRefPubMedGoogle Scholar
  5. 5.
    Chen H, Li M, Campbell RA, Burkhardt K, Zhu D, Li SG, et al. Interference with nuclear factor kappa B and c-Jun NH2-terminal kinase signaling by TRAF6C small interfering RNA inhibits myeloma cell proliferation and enhances apoptosis. Oncogene. 2006;25:6520–7.CrossRefPubMedGoogle Scholar
  6. 6.
    Batten M, Fletcher C, Ng LG, Groom J, Wheway J, Laabi Y, et al. TNF deficiency fails to protect BAFF transgenic mice against autoimmunity and reveals a predisposition to B cell lymphoma. J Immunol. 2004;172:812–22.CrossRefPubMedGoogle Scholar
  7. 7.
    Jiang P, Yueguo W, Huiming H, Hongxiang Y, Mei W, Ju S. B-Lymphocyte stimulator: a new biomarker for multiple myeloma. Eur J Haematol. 2009;82:267–76.CrossRefPubMedGoogle Scholar
  8. 8.
    Wang P, Qian L, Yuan X, Hu C, Wang L, Huang Q, et al. BlyS: a potential hallmark of multiple myeloma. Front Biosci. 2013;18:324–31.CrossRefGoogle Scholar
  9. 9.
    Ju S, Wang Y, Ni H, Wang X, Jiang P, Kong X, et al. Correlation of expression levels of BLyS and its receptors with multiple myeloma. Clin Biochem. 2009;42:387–99.CrossRefPubMedGoogle Scholar
  10. 10.
    Zhong L, Cao F, You Q. Effect of TRAF6 on the biological behavior of human lung adenocarcinoma cell. Tumour Biol. 2013;34:231–9.CrossRefPubMedGoogle Scholar
  11. 11.
    Starczynowski DT, Lockwood WW, Delehouzee S, Chari R, Wegrzyn J, Fuller M, et al. TRAF6 is an amplified oncogene bridging the RAS and NF-kappaB pathways in human lung cancer. J Clin Invest. 2011;121:4095–105.CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Xiao N, Li H, Luo J, Wang R, Chen H, Chen J, et al. Ubiquitin-specific protease 4 (USP4) targets TRAF2 and TRAF6 for deubiquitination and inhibits TNFalpha-induced cancer cell migration. Biochem J. 2012;441:979–86.CrossRefPubMedGoogle Scholar
  13. 13.
    Poblenz AT, Jacoby JJ, Singh S, Darnay BG. Inhibition of RANKL-mediated osteoclast differentiation by selective TRAF6 decoy peptides. Biochem Biophys Res Commun. 2007;359:510–5.CrossRefPubMedGoogle Scholar
  14. 14.
    Hongming H, Jian H. Bortezomib inhibits maturation and function of osteoclasts from PBMCs of patients with multiple myeloma by downregulating TRAF6. Leuk Res. 2009;33:115–22.CrossRefPubMedGoogle Scholar
  15. 15.
    Liu H, Tamashiro S, Baritaki S, Penichet M, Yu Y, Chen H, et al. TRAF6 activation in multiple myeloma: a potential therapeutic target. Clin Lymphoma Myeloma Leuk. 2012;12:155–63.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Romano A, Conticello C, Cavalli M. Immunological dysregulation in multiple myeloma microenvironment. Br J Haematol. 2014;2014:198539.Google Scholar
  17. 17.
    Arcipowski KM, Bishop GA. Roles of the kinase TAK1 in TRAF6-dependent signaling by CD40 and its oncogenic viral mimic, LMP1. PLoS One. 2012;7:e42478.CrossRefPubMedPubMedCentralGoogle Scholar
  18. 18.
    Wi SM, Moon G, Kim J, Kim ST, Shim JH, Chun E, et al. TAK1-ECSIT-TRAF6 complex plays a key role in the TLR4 signal to activate NF-kappaB. J Biol Chem. 2014;289:35205–14.CrossRefPubMedGoogle Scholar
  19. 19.
    Xie P. TRAF molecules in cell signaling and in human diseases. J Mol Signal. 2013;8:7.CrossRefPubMedPubMedCentralGoogle Scholar
  20. 20.
    Novak AJ, Darce JR, Arendt BK, Harder B, Henderson K, Kindsvogel W, et al. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: a mechanism for growth and survival. Blood. 2004;103:689–94.CrossRefPubMedGoogle Scholar
  21. 21.
    Secreto F, Manske M, Price-Troska T, Ziesmer S, Hodge LS, Ansell SM, et al. B-cell activating factor-receptor specific activation of tumor necrosis factor receptor associated factor 6 and the phosphatidyl inositol 3-kinase pathway in lymphoma B cells. Leuk Lymphoma. 2014;5:1884–92.CrossRefGoogle Scholar
  22. 22.
    Shen X, Zhu W, Zhang X, Xu G, Ju S. A role of both NF-kappaB pathways in expression and transcription regulation of BAFF-R gene in multiple myeloma cells. Mol Cell Biochem. 2011;357:21–30.CrossRefPubMedGoogle Scholar
  23. 23.
    Hideshima T, Neri P, Tassone P, Yasui H, Ishitsuka K, Raje N, et al. MLN120B, a novel IkappaB kinase beta inhibitor, blocks multiple myeloma cell growth in vitro and in vivo. Mol Cell Biochem. 2006;12:5887–94.Google Scholar
  24. 24.
    Jourdan M, Moreaux J, Vos JD, Hose D, Mahtouk K, Abouladze M, et al. Targeting NF-kappaB pathway with an IKK2 inhibitor induces inhibition of multiple myeloma cell growth. Br J Haematol. 2007;138:160–8.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media New York 2015

Authors and Affiliations

  • Xinfeng Wang
    • 1
  • Jingjing Wang
    • 1
  • Hong Liu
    • 1
  • Ruirong Xu
    • 1
  • Runsheng Ding
    • 1
  • Shenhua Jiang
    • 1
  • Xudong Wang
    • 2
    Email author
  • Hongming Huang
    • 1
    Email author
  1. 1.Affiliated Hospital of Nantong University, Department of HematologyNantongChina
  2. 2.Center of Clinical Laboratory MedicineAffiliated Hospital of Nantong UniversityNantongChina

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