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首页> 外文期刊>Cellular Signalling >Antiproliferative effects of Bortezomib in endothelial cells transformed by viral G protein-coupled receptor associated to Kaposi's sarcoma
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Antiproliferative effects of Bortezomib in endothelial cells transformed by viral G protein-coupled receptor associated to Kaposi's sarcoma

机译：硼替佐米在与Kaposi的肉瘤相关的病毒G蛋白偶联受体转化内皮细胞中的抗增殖作用

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摘要

The Kaposi's Sarcoma-associated Herpes virus G Protein-Coupled Receptor (vGPCR) is a key molecule in the pathogenesis of Kaposi Sarcoma. We have previously demonstrated that the proteasome inhibitor Bortezomib inhibits NF-KB pathway, which is required for tumor maintenance in endothelial cells that express vGPCR (vGPCR cells). In this work, we further investigated Bortezomib anti-proliferative mechanism of action. We demonstrated that Bortezomib decreases vGPCR cell number in a dose-dependent manner and induces cell morphology changes. Bortezomib decreases ERK1/2 phosphorylation whereas induces the accumulation of MKP-3-a specific ERK1/2 MAP kinase phosphatase in time and concentration dependent manner (1.5-32 h; 0.25-1 nM). The transcription factor FOX01 is activated by dephosphorylation and regulates p21 expression. Here, we demonstrated that Bortezomib increases FOX01 protein and decreases its phosphorylation in a concentration dependent manner (0.25-1 nM). Bortezomib (0.5 nM, 24 h) also increase nuclear FOX01 protein, in line with FOX01 dephosphorylation induced by the drug. Consistent with FOX01 dephosphorylation/activation, p21 mRNA expression is increased by Bortezomib in a MKP-3-dependent way. Bortezomib (0.5 nM, 24 h) also decreases VEGF, an ERK1/2-dependent effect. It is concluded that in vGPCR cells, Bortezomib decreases ERK1/2 and FOX01 phosphorylation through MKP-3 accumulation, leading ERK1/2 deactivation and FOX01 activation respectively and, consequently, to cell proliferation inhibition, p21 induction and VEGF repression. Taken together, all these events contribute to the anti-tumoral effect of Bortezomib. (C) 2017 Elsevier Inc. All rights reserved.
机译：卡波西肉瘤相关疱疹病毒G蛋白偶联受体（vGPCR）是卡波西肉瘤发病机制中的关键分子。我们之前已经证明，蛋白酶体抑制剂硼替佐米抑制NF-KB通路，该通路是表达vGPCR（vGPCR细胞）的内皮细胞维持肿瘤所必需的。在这项工作中，我们进一步研究了硼替佐米的抗增殖作用机制。我们证明硼替佐米以剂量依赖性方式减少vGPCR细胞数量，并诱导细胞形态改变。硼替佐米降低ERK1/2磷酸化，而诱导MKP-3-a特异性ERK1/2 MAP激酶磷酸酶的积累，并呈时间和浓度依赖性（1.5-32h；0.25-1nm）。转录因子FOX01通过去磷酸化激活并调节p21的表达。在此，我们证明硼替佐米以浓度依赖性方式（0.25-1nM）增加FOX01蛋白并降低其磷酸化。硼替佐米（0.5nM，24h）也能增加核FOX01蛋白，与药物诱导的FOX01去磷酸化一致。与FOX01去磷酸化/活化一致，硼替佐米以MKP-3依赖性方式增加p21 mRNA表达。硼替佐米（0.5nM，24h）也能降低ERK1/2依赖的VEGF。结论：在vGPCR细胞中，硼替佐米通过MKP-3的积累降低ERK1/2和FOX01磷酸化，分别导致ERK1/2失活和FOX01激活，从而抑制细胞增殖、p21诱导和VEGF抑制。综上所述，所有这些事件都有助于硼替佐米的抗肿瘤作用。（C） 2017爱思唯尔公司版权所有。

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  • 来源
    《Cellular Signalling》 |2017年第1期|共9页
  • 作者

    Suares A.; Mori Sequeiros Garcia M.; Paz C.; Gonzalez-Pardo V;

  • 作者单位

    Univ Nacl Sur Dept Biol Biochem &

    Pharm Inst Sci Biol &

    Biomed Res INBIOSUR UNSCONICET RA-8000 Bahia Blanca Buenos Aires Argentina;

    Univ Buenos Aires Sch Med Dept Biochem Inst Biomed Res INBIOMED UBA CONICET Paraguay 2155 C1121ABG RA-2155 Buenos Aires DF Argentina;

    Univ Buenos Aires Sch Med Dept Biochem Inst Biomed Res INBIOMED UBA CONICET Paraguay 2155 C1121ABG RA-2155 Buenos Aires DF Argentina;

    Univ Nacl Sur Dept Biol Biochem &

    Pharm Inst Sci Biol &

    Biomed Res INBIOSUR UNSCONICET RA-8000 Bahia Blanca Buenos Aires Argentina;

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  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类 细胞形态学;
  • 关键词

    Bortezomib; MKP-3; ERIC1/2; FOXO1; vGPCR;

    机译：Bortezomib;St. 3;Eric1;Eric1 / 2;Foxo1;VGPCR;

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