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

Abstract

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.

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Abbreviations

4E-BP1:

Eukaryotic initiation factor 4E binding protein 1

Akt:

Protein kinase B (PKB)

BAFF:

B-cell activating factor of the TNF family

BLyS:

B lymphocyte stimulator

BCMA:

B-cell maturation antigen

CDK:

Cyclin-dependent kinase

Erk1/2:

Extracellular signal-related kinases 1/2

MAPK:

Mitogen-activated protein kinase

MKK:

Mitogen-activated protein kinase kinase

mTOR:

Mammalian target of rapamycin

PP2A:

Protein phosphatases 2A

S6K1:

Ribosomal protein S6 kinase 1

SLE:

Systemic lupus erythematosus

TACI:

Transmembrane activator and cyclophilin ligand interactor

TALL-1:

TNF and apoptosis ligand-related leukocyte-expressed ligand1

THANK:

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

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Acknowledgments

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.).

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Correspondence to Shile Huang or Long Chen.

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Zeng, Q., Zhang, H., Qin, J. et al. Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells. Cell. Mol. Life Sci. 72, 4867–4884 (2015). https://doi.org/10.1007/s00018-015-1976-1

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Keywords

  • Rapamycin
  • BAFF
  • mTOR
  • PP2A
  • Erk1/2
  • B cells