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首页> 外文期刊>Cancer letters >Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation
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Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation

机译:血管生成素2通过MSK1激活上调survivin和Ref-1增强HepG2细胞中的阿霉素抗性

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摘要

Angiopoietin2 (Ang2) and its Tie2 receptor have extensive effects on tumor malignancy including angiogenesis and metastasis. In this study, we evaluated the protective effect of Ang2 on doxorubicin-induced apoptosis in HepG2 cells. Ang2 (400. ng/ml) attenuated doxorubicin-mediated cytotoxicity by upregulating the expression of Survivin and Ref-1, which was reversed by a soluble extracellular domain of Tie2. Mechanistic study showed Ang2 activated ERK-MSK cascade to induce histone H3 phosphorylation and inducible gene expression. The stimulatory effect of Ang2 on anti-apoptotic genes was attenuated by either MSK inhibitor (H89) or by overexpression of a kinase-deficient MSK1. Activated MSK1 phosphorylated the CREB at Ser133 and phosho-CREB was recruited to Ref-1 promoter rapidly to initiate the gene expression. Moreover, knockdown of MSK1 by specific siRNA also attenuated the pro-survival activity of Ang2 and CREB phosphorylation. Hence, our study suggests the existence of an Ang2-ERK-MSK signaling axis mediating survival responses and drug resistance of tumor cells.
机译:血管生成素2(Ang2)及其Tie2受体对肿瘤恶性肿瘤具有广泛的影响,包括血管生成和转移。在这项研究中,我们评估了Ang2对阿霉素诱导的HepG2细胞凋亡的保护作用。 Ang2(400. ng / ml)通过上调Survivin和Ref-1的表达来减弱阿霉素介导的细胞毒性,后者被Tie2的可溶性胞外域逆转。机理研究表明,Ang2激活ERK-MSK级联反应可诱导组蛋白H3磷酸化和可诱导的基因表达。 Ang2对抗凋亡基因的刺激作用被MSK抑制剂(H89)或激酶缺失的MSK1的过表达减弱了。激活的MSK1使Ser133处的CREB磷酸化,并迅速将phosho-CREB募集到Ref-1启动子以启动基因表达。此外,通过特异性siRNA敲低MSK1也减弱了Ang2的生存前活性和CREB磷酸化。因此,我们的研究表明存在介导肿瘤细胞存活反应和耐药性的Ang2-ERK-MSK信号轴。

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