Rapamycin inhibits BAFF-stimulated cell proliferation and survival by suppressing mTOR-mediated PP2A-Erk1/2 signaling pathway in normal and neoplastic B-lymphoid cells.
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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Rapamycin 通过抑制正常和肿瘤性 B 淋巴细胞中 mTOR 介导的 PP2A-Erk1/2 信号通路来抑制 BAFF 刺激的细胞增殖和存活。
DOI：
10.1007/s00018-015-1976-1
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发表时间：
2015-12
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B细胞活化因子（BAFF）不仅参与正常B细胞的生理活动，而且参与恶性肿瘤和自身免疫性疾病相关的侵袭性B细胞的病理生理活动。雷帕霉素是一种亲脂性大环内酯类抗生素，最近已被证明可有效治疗人类红斑狼疮。然而，雷帕霉素如何抑制BAFF刺激的B细胞增殖和存活尚未完全阐明。在这里，我们表明，雷帕霉素抑制人可溶性BAFF（hsBAFF）诱导的细胞增殖和生存在正常和B淋巴（Raji和Daudi）细胞通过激活PP 2A和Erk 1/2失活。PD 98059预处理、Erk 1/2下调、显性阴性MKK 1表达或野生型PP 2A过表达增强了雷帕霉素对hsBAFF激活的Erk 1/2和B细胞增殖/活力的抑制，而组成型活性MKK 1表达、冈田酸抑制PP 2A或显性阴性PP 2A表达减弱了雷帕霉素的抑制作用。此外，雷帕霉素抗性和激酶活性mTOR（mTOR-T）的表达，而不是雷帕霉素抗性和激酶死亡mTOR-T（mTOR-TE）的表达，赋予了对雷帕霉素对PP 2A、Erk 1/2和B细胞增殖/活力的作用的抗性，这意味着涉及mTOR依赖性机制。研究结果表明，雷帕霉素通过靶向正常和肿瘤性B淋巴细胞中mTOR介导的PP 2A-Erk 1/2信号通路抑制BAFF刺激的细胞增殖/存活。我们的数据强调，雷帕霉素可用于预防过度BAFF诱导的侵袭性B细胞恶性肿瘤和自身免疫性疾病。
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.