BAFF is involved in macrophage-induced bortezomib resistance in myeloma

Jing Chen, Donghua He, Qingxiao Chen, Xing Guo, Li Yang, Xuanru Lin, Yi Li, Wenjun Wu, Yang Yang, Jingsong He, Enfan Zhang, Qing Yi, Zhen Cai

Research output: Contribution to journalArticle

4 Scopus citations

Abstract

We aimed to characterize the role of B-cell activating factor (BAFF) in macrophage-mediated resistance of multiple myeloma (MM) cells to bortezomib (bort), and to further understand the molecular mechanisms involved in the process. First, we detected BAFF and its three receptors on myeloma cells and macrophages using the quantitative reverse transcriptase-polymerase chain reaction and flow cytometry. The secretion of BAFF was tested in patients with MM, MM cell lines, and macrophages. The ability of macrophages to protect MM cells from bort-induced apoptosis was significantly attenuated using BAFF-neutralizing antibody in the co-culture system or knocking down the expression of BAFF in macrophages with small interfering RNA. We also showed that the MM-macrophage interaction through BAFF and its receptors was primarily mediated by the activation of Src, Erk1/2, Akt, and nuclear factor kappa B signaling and the suppression of caspase activation induced by bort. Our data demonstrated that BAFF played a functional role in the macrophage-mediated resistance of MM cells to bort, suggesting that targeting BAFF may provide a basis for the molecular- and immune-targeted therapeutic approach.

Original languageEnglish (US)
Pages (from-to)e3161
JournalCell death & disease
Volume8
Issue number11
DOIs
StatePublished - Nov 2 2017

Keywords

  • Animals
  • Antibodies, Neutralizing/immunology
  • Antineoplastic Agents/pharmacology
  • Apoptosis/drug effects
  • B-Cell Activating Factor/antagonists & inhibitors
  • Bortezomib/pharmacology
  • Cell Differentiation/drug effects
  • Cell Line, Tumor
  • Drug Resistance, Neoplasm
  • Humans
  • Leukocytes, Mononuclear/cytology
  • Macrophage Colony-Stimulating Factor/pharmacology
  • Macrophages/cytology
  • Mice
  • Mice, Inbred NOD
  • Mice, SCID
  • Mitogen-Activated Protein Kinase 1/metabolism
  • Mitogen-Activated Protein Kinase 3/metabolism
  • Multiple Myeloma/drug therapy
  • Proto-Oncogene Proteins c-akt/metabolism
  • Signal Transduction/drug effects

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