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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

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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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Authors and Affiliations

  1. Jiangsu Key Laboratory for Molecular and Medical Biotechnology, Jiangsu Key Laboratory for Microbes and Functional Genomics, College of Life Sciences, Nanjing Normal University, 1 Wenyuan Road, Chixia District, Nanjing, 210023, Jiangsu, People’s Republic of China

    Qingyu Zeng, Hai Zhang, Jiamin Qin, Zhigang Xu, Lin Gui, Beibei Liu, Chunxiao Liu, Chong Xu, Wen Liu, Shuangquan Zhang & Long Chen

  2. Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA

    Shile Huang

  3. Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA

    Shile Huang

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  1. Qingyu Zeng
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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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