title: 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.
authors.affiliation: 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.
authors.forename: Qingyu
authors.initials: Q
authors.lastname: Zeng
authors.affiliation: 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.
authors.forename: Hai
authors.initials: H
authors.lastname: Zhang
authors.affiliation: 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.
authors.forename: Jiamin
authors.initials: J
authors.lastname: Qin
authors.affiliation: 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.
authors.forename: Zhigang
authors.initials: Z
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Lin
authors.initials: L
authors.lastname: Gui
authors.affiliation: 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.
authors.forename: Beibei
authors.initials: B
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Chunxiao
authors.initials: C
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Chong
authors.initials: C
authors.lastname: Xu
authors.affiliation: 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.
authors.forename: Wen
authors.initials: W
authors.lastname: Liu
authors.affiliation: 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.
authors.forename: Shuangquan
authors.initials: S
authors.lastname: Zhang
authors.affiliation: Department of Biochemistry and Molecular Biology, Louisiana State University Health Sciences Center, 1501 Kings Highway, Shreveport, LA, 71130-3932, USA. shuan1@lsuhsc.edu.|Feist-Weiller Cancer Center, Louisiana State University Health Sciences Center, Shreveport, LA, 71130-3932, USA. shuan1@lsuhsc.edu.
authors.forename: Shile
authors.initials: S
authors.lastname: Huang
authors.affiliation: 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. lchen@njnu.edu.cn.
authors.forename: Long
authors.initials: L
authors.lastname: Chen
mesh_terms: D000818:Animals; D053264:B-Cell Activating Factor / Q000378:metabolism / Q000502:physiology*; D001402:B-Lymphocytes / Q000187:drug effects* / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D015536:Down-Regulation; D006801:Humans; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D015398:Signal Transduction; D020123:Sirolimus / Q000494:pharmacology*; D058570:TOR Serine-Threonine Kinases / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
chemical_list: D053264:B-Cell Activating Factor; C505719:TNFSF13B protein, human; C546842:MTOR protein, human; D058570:TOR Serine-Threonine Kinases; D020123:Sirolimus
keywords: B cells; BAFF; Erk1/2; PP2A; Rapamycin; mTOR