Cellular and Molecular Life Sciences

, Volume 72, Issue 24, pp 4867–4884 | Cite as

Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells

  • Qingyu Zeng
  • Hai Zhang
  • Jiamin Qin
  • Zhigang Xu
  • Lin Gui
  • Beibei Liu
  • Chunxiao Liu
  • Chong Xu
  • Wen Liu
  • Shuangquan Zhang
  • Shile Huang
  • Long Chen
Research Article


B-cell activating factor (BAFF) is involved in not only physiology of normal B cells, but also pathophysiology of aggressive B cells related to malignant and autoimmune diseases. Rapamycin, a lipophilic macrolide antibiotic, has recently shown to be effective in the treatment of human lupus erythematosus. However, how rapamycin inhibits BAFF-stimulated B-cell proliferation and survival has not been fully elucidated. Here, we show that rapamycin inhibited human soluble BAFF (hsBAFF)-induced cell proliferation and survival in normal and B-lymphoid (Raji and Daudi) cells by activation of PP2A and inactivation of Erk1/2. Pretreatment with PD98059, down-regulation of Erk1/2, expression of dominant negative MKK1, or overexpression of wild-type PP2A potentiated rapamycin’s suppression of hsBAFF-activated Erk1/2 and B-cell proliferation/viability, whereas expression of constitutively active MKK1, inhibition of PP2A by okadaic acid, or expression of dominant negative PP2A attenuated the inhibitory effects of rapamycin. Furthermore, expression of a rapamycin-resistant and kinase-active mTOR (mTOR-T), but not a rapamycin-resistant and kinase-dead mTOR-T (mTOR-TE), conferred resistance to rapamycin’s effects on PP2A, Erk1/2 and B-cell proliferation/viability, implying mTOR-dependent mechanism involved. The findings indicate that rapamycin inhibits BAFF-stimulated cell proliferation/survival by targeting mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Our data highlight that rapamycin may be exploited for preventing excessive BAFF-induced aggressive B-cell malignancies and autoimmune diseases.


Rapamycin BAFF mTOR PP2A Erk1/2 B cells 



Eukaryotic initiation factor 4E binding protein 1


Protein kinase B (PKB)


B-cell activating factor of the TNF family


B lymphocyte stimulator


B-cell maturation antigen


Cyclin-dependent kinase


Extracellular signal-related kinases 1/2


Mitogen-activated protein kinase


Mitogen-activated protein kinase kinase


Mammalian target of rapamycin


Protein phosphatases 2A


Ribosomal protein S6 kinase 1


Systemic lupus erythematosus


Transmembrane activator and cyclophilin ligand interactor


TNF and apoptosis ligand-related leukocyte-expressed ligand1


TNF homologue that activates apoptosis, nuclear factor κB, and c-Jun NH2-terminal kinase



This work was supported in part by the grants from National Natural Science Foundation of China (No. 31172083; L.C.), NIH (CA115414; S.H.), Project for the Priority Academic Program Development and the Natural Science Foundation of Jiangsu Higher Education Institutions of China (10KJA180027; L.C.), American Cancer Society (RSG-08-135-01-CNE; S.H.), Louisiana Board of Regents (NSF-2009-PFUND-144; S.H.), and Innovative Research Program of Jiangsu College Graduate of China (No. KYLX_0714; Q.Z.).

Conflict of interest

The authors declare that they have no conflict of interest.


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Copyright information

© Springer Basel 2015

Authors and Affiliations

  • Qingyu Zeng
    • 1
  • Hai Zhang
    • 1
  • Jiamin Qin
    • 1
  • Zhigang Xu
    • 1
  • Lin Gui
    • 1
  • Beibei Liu
    • 1
  • Chunxiao Liu
    • 1
  • Chong Xu
    • 1
  • Wen Liu
    • 1
  • Shuangquan Zhang
    • 1
  • Shile Huang
    • 2
    • 3
  • Long Chen
    • 1
  1. 1.Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life SciencesNanjing Normal UniversityNanjingPeople’s Republic of China
  2. 2.Department of Biochemistry and Molecular BiologyLouisiana State University Health Sciences CenterShreveportUSA
  3. 3.Feist-Weiller Cancer CenterLouisiana State University Health Sciences CenterShreveportUSA

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