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首页> 外文期刊>Cellular Signalling >Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells
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Down-regulation of growth factor-stimulated MAP kinase signaling in cytotoxic drug-resistant human neuroblastoma cells

机译:细胞毒性药物耐药的人神经母细胞瘤细胞中生长因子刺激的MAP激酶信号下调

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The mitogen-activated protein kinase (MAPk) signaling pathway, which plays a critical role in the proliferation of mammalian cells. is frequently up-regulated in human tumors and may contribute to the transformed phenotype. Since a major limitation of current cancer chemotherapy is prevalent resistance to cytotoxic drugs. this study determined whether alterations in growth factor signaling through MAPk may contribute to this phenomenon in human neuroblastoma cell lines. Drug-resistant SKNSH cell lines were established by long-term incubation with increasing concentrations to 10(-6) M doxorubicin (SKNSH rDOX6) or MDL 28842 (SKNSH rMDL6). The expression of epidermal growth factor receptor (EGFR) and epidermal growth factor (EGF)-induced EGFR tyrosine phosphorylation were lower in drug-resistant SKNSH cells than their wild-type counterparts. In SKNSH rDOX6 cells, decreased activation and reduced nuclear translocation of MAPk in response to EGF, or lysophosphatidic acid (LPA), or phorbol 12-myristate 13-acetate (PMA), were observed. In SKNSH rMDL6 cells, although MAPk could be activated to wild-type levels by ligand stimulation. the translocation of acticle MAPk to the nucleus was also reduced. These results suggest that resistance to cytotoxic drugs in human neuroblastoma cell lines is associated with a decrease in growth factor signaling through the MAPk pathway. (C) 2001 Elsevier Science Inc. All rights reserved. [References: 49]
机译:有丝分裂原激活的蛋白激酶(MAPk)信号通路,在哺乳动物细胞的增殖中起关键作用。在人类肿瘤中,其通常被上调并且可能有助于转化的表型。由于当前癌症化学疗法的主要局限性是对细胞毒性药物的普遍耐药性。这项研究确定了通过MAPk进行的生长因子信号转导的改变是否可能在人类神经母细胞瘤细胞系中造成了这种现象。通过以浓度增加至10(-6)M阿霉素(SKNSH rDOX6)或MDL 28842(SKNSH rMDL6)的浓度长期孵育来建立耐药SKNSH细胞系。耐药SKNSH细胞中表皮生长因子受体(EGFR)和表皮生长因子(EGF)诱导的EGFR酪氨酸磷酸化的表达低于野生型。在SKNSH rDOX6细胞中,观察到响应EGF或溶血磷脂酸(LPA)或佛波醇12-肉豆蔻酸酯13-乙酸酯(PMA)而降低了MAPk的活化和核转运。在SKNSH rMDL6细胞中,尽管MAPk可通过配体刺激被激活至野生型水平。 acticle MAPk向核的移位也减少了。这些结果表明,对人神经母细胞瘤细胞系中细胞毒药物的耐药性与通过MAPk途径的生长因子信号传导的减少有关。 (C)2001 Elsevier Science Inc.保留所有权利。 [参考:49]

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