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.
Keywords:
Angiopoietin-2; Apoptosis; CREB; Doxorubicin; HepG2 cells; MSK.
Copyright © 2013 Elsevier Ireland Ltd. All rights reserved.
Publication types
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Research Support, Non-U.S. Gov't
MeSH terms
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Angiopoietin-2 / metabolism*
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Antibiotics, Antineoplastic / pharmacology*
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Apoptosis / drug effects
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Binding Sites
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Carcinoma, Hepatocellular / enzymology*
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Carcinoma, Hepatocellular / genetics
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Carcinoma, Hepatocellular / pathology
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Cyclic AMP Response Element-Binding Protein / metabolism
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DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
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Dose-Response Relationship, Drug
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Doxorubicin / pharmacology*
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Drug Resistance, Neoplasm*
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Enzyme Activation
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Gene Expression Regulation, Neoplastic
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Hep G2 Cells
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Histones / metabolism
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Humans
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Inhibitor of Apoptosis Proteins / metabolism*
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Liver Neoplasms / enzymology*
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Liver Neoplasms / genetics
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Liver Neoplasms / pathology
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Mitochondria / drug effects
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Mitochondria / metabolism
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Oxidative Stress / drug effects
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Phosphorylation
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Promoter Regions, Genetic
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Protein Kinase Inhibitors / pharmacology
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RNA Interference
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Receptor, TIE-2 / metabolism
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Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
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Ribosomal Protein S6 Kinases, 90-kDa / genetics
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Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
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Survivin
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Transfection
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Up-Regulation
Substances
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Angiopoietin-2
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Antibiotics, Antineoplastic
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BIRC5 protein, human
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CREB1 protein, human
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Cyclic AMP Response Element-Binding Protein
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Histones
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Inhibitor of Apoptosis Proteins
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Protein Kinase Inhibitors
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Survivin
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Doxorubicin
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Receptor, TIE-2
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Ribosomal Protein S6 Kinases, 90-kDa
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mitogen and stress-activated protein kinase 1
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APEX1 protein, human
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DNA-(Apurinic or Apyrimidinic Site) Lyase