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

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.

Keywords

Rapamycin BAFF mTOR PP2A Erk1/2 B cells 

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

References

  1. 1.
    Schneider P, MacKay F, Steiner V, Hofmann K, Bodmer JL, Holler N et al (1999) BAFF, a novel ligand of the tumor necrosis factor family, stimulates B cell growth. J Exp Med 189:1747–1756PubMedCentralCrossRefPubMedGoogle Scholar
  2. 2.
    Henley T, Kovesdi D, Turner M (2008) B-cell responses to B-cell activation factor of the TNF family (BAFF) are impaired in the absence of PI3K delta. Eur J Immunol 38:3543–3548CrossRefPubMedGoogle Scholar
  3. 3.
    Moore PA, Belvedere O, Orr A, Pieri K, LaFleur DW, Feng P et al (1999) BLyS: member of the tumor necrosis factor family and B lymphocyte stimulator. Science 285:260–263CrossRefPubMedGoogle Scholar
  4. 4.
    Mueller CG, Boix C, Kwan WH, Daussy C, Fournier E, Fridman WH et al (2007) Critical role of monocytes to support normal B cell and diffuse large B cell lymphoma survival and proliferation. J Leukoc Biol 82:567–575CrossRefPubMedGoogle Scholar
  5. 5.
    Mackay F, Silveira PA, Brink R (2007) B cells and the BAFF/APRIL axis: fast-forward on autoimmunity and signaling. Curr Opin Immunol 19:327–336CrossRefPubMedGoogle Scholar
  6. 6.
    Schneider P, Tschopp J (2003) BAFF and the regulation of B cell survival. Immunol Lett 88:57–62CrossRefPubMedGoogle Scholar
  7. 7.
    Fu L, Lin-Lee YC, Pham LV, Tamayo AT, Yoshimura LC, Ford RJ (2009) BAFF-R promotes cell proliferation and survival through interaction with IKKbeta and NF-κB/c-Rel in the nucleus of normal and neoplastic B-lymphoid cells. Blood 113:4627–4636PubMedCentralCrossRefPubMedGoogle Scholar
  8. 8.
    Moisini I, Davidson A (2009) BAFF: a local and systemic target in autoimmune diseases. Clin Exp Immunol 158:155–163PubMedCentralCrossRefPubMedGoogle Scholar
  9. 9.
    Mackay F, Ambrose C (2003) The TNF family members BAFF and APRIL: the growing complexity. Cytokine Growth Factor Rev 14:311–324CrossRefPubMedGoogle Scholar
  10. 10.
    Zhang X, Park CS, Yoon SO, Li L, Hsu YM, Ambrose C et al (2005) BAFF supports human B cell differentiation in the lymphoid follicles through distinct receptors. Int Immunol 17:779–788CrossRefPubMedGoogle Scholar
  11. 11.
    Patke A, Mecklenbrauker I, Erdjument-Bromage H, Tempst P, Tarakhovsky A (2006) BAFF controls B cell metabolic fitness through a PKC beta- and Akt-dependent mechanism. J Exp Med 203:2551–2562PubMedCentralCrossRefPubMedGoogle Scholar
  12. 12.
    Sanz I, Lee FE (2010) B cells as therapeutic targets in SLE. Nat Rev Rheumatol 6:326–337PubMedCentralCrossRefPubMedGoogle Scholar
  13. 13.
    Bosello S, Youinou P, Daridon C, Tolusso B, Bendaoud B, Pietrapertosa D et al (2008) Concentrations of BAFF correlate with autoantibody levels, clinical disease activity, and response to treatment in early rheumatoid arthritis. J Rheumatol 35:1256–1264PubMedGoogle Scholar
  14. 14.
    Zhang J, Roschke V, Baker KP, Wang Z, Alarcon GS, Fessler BJ et al (2001) Cutting edge: a role for B lymphocyte stimulator in systemic lupus erythematosus. J Immunol 166:6–10CrossRefPubMedGoogle Scholar
  15. 15.
    Sasaki Y, Derudder E, Hobeika E, Pelanda R, Reth M, Rajewsky K et al (2006) Canonical NF-kappaB activity, dispensable for B cell development, replaces BAFF-receptor signals and promotes B cell proliferation upon activation. Immunity 24:729–739CrossRefPubMedGoogle Scholar
  16. 16.
    Cornec D, Devauchelle-Pensec V, Tobon GJ, Pers JO, Jousse-Joulin S, Saraux A (2012) B cells in Sjogren’s syndrome: from pathophysiology to diagnosis and treatment. J Autoimmun 39:161–167CrossRefPubMedGoogle Scholar
  17. 17.
    Ramanujam M, Davidson A (2008) BAFF blockade for systemic lupus erythematosus: will the promise be fulfilled? Immunol Rev 223:156–174CrossRefPubMedGoogle Scholar
  18. 18.
    Otipoby KL, Sasaki Y, Schmidt-Supprian M, Patke A, Gareus R, Pasparakis M et al (2008) BAFF activates Akt and Erk through BAFF-R in an IKK1-dependent manner in primary mouse B cells. Proc Natl Acad Sci USA 105:12435–12438PubMedCentralCrossRefPubMedGoogle Scholar
  19. 19.
    Woodland RT, Fox CJ, Schmidt MR, Hammerman PS, Opferman JT, Korsmeyer SJ et al (2008) Multiple signaling pathways promote B lymphocyte stimulator dependent B-cell growth and survival. Blood 111:750–760PubMedCentralCrossRefPubMedGoogle Scholar
  20. 20.
    Fernandez D, Bonilla E, Mirza N, Niland B, Perl A (2006) Rapamycin reduces disease activity and normalizes T cell activation-induced calcium fluxing in patients with systemic lupus erythematosus. Arthritis Rheum 54:2983–2988PubMedCentralCrossRefPubMedGoogle Scholar
  21. 21.
    Laplante M, Sabatini DM (2012) mTOR signaling in growth control and disease. Cell 149:274–293PubMedCentralCrossRefPubMedGoogle Scholar
  22. 22.
    Shimobayashi M, Hall MN (2014) Making new contacts: the mTOR network in metabolism and signalling crosstalk. Nat Rev Mol Cell Biol 15:155–162CrossRefPubMedGoogle Scholar
  23. 23.
    Fernandez D, Perl A (2010) mTOR signaling: a central pathway to pathogenesis in systemic lupus erythematosus? Discov Med 9:173–178PubMedCentralPubMedGoogle Scholar
  24. 24.
    Ke Z, Liang D, Zeng Q, Ren Q, Ma H, Gui L et al (2013) hsBAFF promotes proliferation and survival in cultured B lymphocytes via calcium signaling activation of mTOR pathway. Cytokine 62:310–321CrossRefPubMedGoogle Scholar
  25. 25.
    Junttila MR, Li SP, Westermarck J (2008) Phosphatase-mediated crosstalk between MAPK signaling pathways in the regulation of cell survival. FASEB J 22:954–965CrossRefPubMedGoogle Scholar
  26. 26.
    Shi Y (2009) Serine/threonine phosphatases: mechanism through structure. Cell 139:468–484CrossRefPubMedGoogle Scholar
  27. 27.
    Sunahori K, Nagpal K, Hedrich CM, Mizui M, Fitzgerald LM, Tsokos GC (2013) The catalytic subunit of protein phosphatase 2A (PP2Ac) promotes DNA hypomethylation by suppressing the phosphorylated mitogen-activated protein kinase/extracellular signal-regulated kinase (ERK) kinase (MEK)/phosphorylated ERK/DNMT1 protein pathway in T-cells from controls and systemic lupus erythematosus patients. J Biol Chem 288:21936–21944PubMedCentralCrossRefPubMedGoogle Scholar
  28. 28.
    Katsiari CG, Kyttaris VC, Juang YT, Tsokos GC (2005) Protein phosphatase 2A is a negative regulator of IL-2 production in patients with systemic lupus erythematosus. J Clin Invest 115:3193–3204PubMedCentralCrossRefPubMedGoogle Scholar
  29. 29.
    Endong L, Shijie J, Sonobe Y, Di M, Hua L, Kawanokuchi J et al (2011) The gap-junction inhibitor carbenoxolone suppresses the differentiation of Th17 cells through inhibition of IL-23 expression in antigen presenting cells. J Neuroimmunol 240–241:58–64CrossRefPubMedGoogle Scholar
  30. 30.
    Crispin JC, Apostolidis SA, Rosetti F, Keszei M, Wang N, Terhorst C et al (2012) Cutting edge: protein phosphatase 2A confers susceptibility to autoimmune disease through an IL-17-dependent mechanism. J Immunol 188:3567–3571PubMedCentralCrossRefPubMedGoogle Scholar
  31. 31.
    Crispin JC, Hedrich CM, Tsokos GC (2013) Gene-function studies in systemic lupus erythematosus. Nat Rev Rheumatol 9:476–484CrossRefPubMedGoogle Scholar
  32. 32.
    Lin MY, Zal T, Ch’en IL, Gascoigne NR, Hedrick SM (2005) A pivotal role for the multifunctional calcium/calmodulin-dependent protein kinase II in T cells: from activation to unresponsiveness. J Immunol 174:5583–5592CrossRefPubMedGoogle Scholar
  33. 33.
    Liang JQ, Zhang W, Wen L, Gao W, Zhang SQ, Chen L (2009) hsBAFF-upregulated intracellular free Ca2+ homeostasis regulates ERK1/2 activity and cell proliferation in B cells in vitro. Physiol Res 58:411–418PubMedGoogle Scholar
  34. 34.
    Liang D, Zeng Q, Xu Z, Zhang H, Gui L, Xu C et al (2014) BAFF activates Erk1/2 promoting cell proliferation and survival by Ca2+-CaMKII-dependent inhibition of PP2A in normal and neoplastic B-lymphoid cells. Biochem Pharmacol 87:332–343PubMedCentralCrossRefPubMedGoogle Scholar
  35. 35.
    Peterson RT, Desai BN, Hardwick JS, Schreiber SL (1999) Protein phosphatase 2A interacts with the 70-kDa S6 kinase and is activated by inhibition of FKBP12-rapamycin associated protein. Proc Natl Acad Sci USA 96:4438–4442PubMedCentralCrossRefPubMedGoogle Scholar
  36. 36.
    Cao P, Mei JJ, Diao ZY, Zhang S (2005) Expression, refolding, and characterization of human soluble BAFF synthesized in Escherichia coli. Protein Expr Purif 41:199–206CrossRefPubMedGoogle Scholar
  37. 37.
    Liu L, Chen L, Luo Y, Chen W, Zhou H, Xu B et al (2010) Rapamycin inhibits IGF-1 stimulated cell motility through PP2A pathway. PLoS ONE 5:e10578PubMedCentralCrossRefPubMedGoogle Scholar
  38. 38.
    Chen L, Liu L, Yin J, Luo Y, Huang S (2009) Hydrogen peroxide-induced neuronal apoptosis is associated with inhibition of protein phosphatase 2A and 5, leading to activation of MAPK pathway. Int J Biochem Cell Biol 41:1284–1295CrossRefPubMedGoogle Scholar
  39. 39.
    Liu L, Luo Y, Chen L, Shen T, Xu B, Chen W et al (2010) Rapamycin inhibits cytoskeleton reorganization and cell motility by suppressing RhoA expression and activity. J Biol Chem 285:38362–38373PubMedCentralCrossRefPubMedGoogle Scholar
  40. 40.
    Chen L, Liu L, Luo Y, Huang S (2008) MAPK and mTOR pathways are involved in cadmium-induced neuronal apoptosis. J Neurochem 105:251–261CrossRefPubMedGoogle Scholar
  41. 41.
    Janssens V, Goris J, Van Hoof C (2005) PP2A: the expected tumor suppressor. Curr Opin Genet Dev 15:34–41CrossRefPubMedGoogle Scholar
  42. 42.
    Janssens V, Goris J (2001) Protein phosphatase 2A: a highly regulated family of serine/threonine phosphatases implicated in cell growth and signalling. Biochem J 353:417–439PubMedCentralCrossRefPubMedGoogle Scholar
  43. 43.
    Malumbres M, Barbacid M (2009) Cell cycle, CDKs and cancer: a changing paradigm. Nat Rev Cancer 9:153–166CrossRefPubMedGoogle Scholar
  44. 44.
    Decker T, Hipp S, Ringshausen I, Bogner C, Oelsner M, Schneller F et al (2003) Rapamycin-induced G1 arrest in cycling B-CLL cells is associated with reduced expression of cyclin D3, cyclin E, cyclin A, and survivin. Blood 101:278–285CrossRefPubMedGoogle Scholar
  45. 45.
    Vaysberg M, Balatoni CE, Nepomuceno RR, Krams SM, Martinez OM (2007) Rapamycin inhibits proliferation of Epstein-Barr virus-positive B-cell lymphomas through modulation of cell-cycle protein expression. Transplantation 83:1114–1121CrossRefPubMedGoogle Scholar
  46. 46.
    Klein EA, Assoian RK (2008) Transcriptional regulation of the cyclin D1 gene at a glance. J Cell Sci 121:3853–3857PubMedCentralCrossRefPubMedGoogle Scholar
  47. 47.
    Leontieva OV, Demidenko ZN, Blagosklonny MV (2013) MEK drives cyclin D1 hyperelevation during geroconversion. Cell Death Differ 20:1241–1249PubMedCentralCrossRefPubMedGoogle Scholar
  48. 48.
    Moon DO, Park C, Heo MS, Park YM, Choi YH, Kim GY (2007) PD98059 triggers G1 arrest and apoptosis in human leukemic U937 cells through downregulation of Akt signal pathway. Int Immunopharmacol 7:36–45CrossRefPubMedGoogle Scholar
  49. 49.
    Hardie DG, Haystead TA, Sim AT (1991) Use of okadaic acid to inhibit protein phosphatases in intact cells. Methods Enzymol 201:469–476CrossRefPubMedGoogle Scholar
  50. 50.
    Erbay E, Chen J (2001) The mammalian target of rapamycin regulates C2C12 myogenesis via a kinase-independent mechanism. J Biol Chem 276:36079–36082CrossRefPubMedGoogle Scholar
  51. 51.
    Kaneko T, Amano H, Kawano S, Minowa K, Ando S, Watanabe T et al (2014) Increased serum concentration of BAFF/APRIL and IgA2 subclass in patients with mixed connective tissue disease complicated by interstitial lung disease. Mod Rheumatol 24:310–315CrossRefPubMedGoogle Scholar
  52. 52.
    Zhou H, Luo Y, Huang S (2010) Updates of mTOR inhibitors. Anticancer Agents Med Chem 10:571–581PubMedCentralCrossRefPubMedGoogle Scholar
  53. 53.
    Haiat S, Billard C, Quiney C, Ajchenbaum-Cymbalista F, Kolb JP (2006) Role of BAFF and APRIL in human B-cell chronic lymphocytic leukaemia. Immunology 118:281–292PubMedCentralCrossRefPubMedGoogle Scholar
  54. 54.
    Huang X, Di Liberto M, Cunningham AF, Kang L, Cheng S, Ely S et al (2004) Homeostatic cell-cycle control by BLyS: induction of cell-cycle entry but not G1/S transition in opposition to p18INK4c and p27Kip1. Proc Natl Acad Sci USA 101:17789–17794PubMedCentralCrossRefPubMedGoogle Scholar
  55. 55.
    Tirado OM, Mateo-Lozano S, Notario V (2005) Rapamycin induces apoptosis of JN-DSRCT-1 cells by increasing the Bax : Bcl-xL ratio through concurrent mechanisms dependent and independent of its mTOR inhibitory activity. Oncogene 24:3348–3357CrossRefPubMedGoogle Scholar
  56. 56.
    Vega F, Medeiros LJ, Leventaki V, Atwell C, Cho-Vega JH, Tian L et al (2006) Activation of mammalian target of rapamycin signaling pathway contributes to tumor cell survival in anaplastic lymphoma kinase-positive anaplastic large cell lymphoma. Cancer Res 66:6589–6597CrossRefPubMedGoogle Scholar
  57. 57.
    Peponi E, Drakos E, Reyes G, Leventaki V, Rassidakis GZ, Medeiros LJ (2006) Activation of mammalian target of rapamycin signaling promotes cell cycle progression and protects cells from apoptosis in mantle cell lymphoma. Am J Pathol 169:2171–2180PubMedCentralCrossRefPubMedGoogle Scholar
  58. 58.
    Han X, Xu B, Beevers CS, Odaka Y, Chen L, Liu L et al (2012) Curcumin inhibits protein phosphatases 2A and 5, leading to activation of mitogen-activated protein kinases and death in tumor cells. Carcinogenesis 33:868–875PubMedCentralCrossRefPubMedGoogle Scholar
  59. 59.
    Bakema JE, Bakker A, de Haij S, Honing H, Bracke M, Koenderman L et al (2008) Inside-out regulation of Fc alpha RI (CD89) depends on PP2A. J Immunol 181:4080–4088CrossRefPubMedGoogle Scholar
  60. 60.
    Crispin JC, Apostolidis SA, Finnell MI, Tsokos GC (2011) Induction of PP2A Bbeta, a regulator of IL-2 deprivation-induced T-cell apoptosis, is deficient in systemic lupus erythematosus. Proc Natl Acad Sci USA 108:12443–12448PubMedCentralCrossRefPubMedGoogle Scholar
  61. 61.
    Roskoski R Jr (2012) ERK1/2 MAP kinases: structure, function, and regulation. Pharmacol Res 66:105–143CrossRefPubMedGoogle Scholar
  62. 62.
    Shu L, Zhang X, Houghton PJ (2002) Myogenic differentiation is dependent on both the kinase function and the N-terminal sequence of mammalian target of rapamycin. J Biol Chem 277:16726–16732CrossRefPubMedGoogle Scholar

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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