Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation |
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Authors: | Tao Li Zhiqiang Liu Kesheng Jiang Qin Ruan |
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Institution: | 1. Department of Biology, College of Chemistry and Life Sciences, Zhejiang Normal University, 688 Yingbin Road, Jinhua, Zhejiang 321004, China;2. Department of Lymphoma and Myeloma, Division of Cancer Medicine, Center for Cancer Immunology Research, The University of Texas MD Anderson Cancer Center, Houston, TX 77054, USA;3. College of Xingzhi, Zhejiang Normal University, 688 Yingbin Road, Jinhua, Zhejiang 321004, China |
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Abstract: | 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. |
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Keywords: | Angiopoietin-2 HepG2 cells Doxorubicin Apoptosis MSK CREB |
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