Angiopoietin2 enhances doxorubin resistance in HepG2 cells by upregulating survivin and Ref-1 via MSK1 activation

Cancer Lett. 2013 Sep 1;337(2):276-84. doi: 10.1016/j.canlet.2013.04.028. Epub 2013 May 2.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Angiopoietin-2 / metabolism*
  • Antibiotics, Antineoplastic / pharmacology*
  • Apoptosis / drug effects
  • Binding Sites
  • Carcinoma, Hepatocellular / enzymology*
  • Carcinoma, Hepatocellular / genetics
  • Carcinoma, Hepatocellular / pathology
  • Cyclic AMP Response Element-Binding Protein / metabolism
  • DNA-(Apurinic or Apyrimidinic Site) Lyase / metabolism*
  • Dose-Response Relationship, Drug
  • Doxorubicin / pharmacology*
  • Drug Resistance, Neoplasm*
  • Enzyme Activation
  • Gene Expression Regulation, Neoplastic
  • Hep G2 Cells
  • Histones / metabolism
  • Humans
  • Inhibitor of Apoptosis Proteins / metabolism*
  • Liver Neoplasms / enzymology*
  • Liver Neoplasms / genetics
  • Liver Neoplasms / pathology
  • Mitochondria / drug effects
  • Mitochondria / metabolism
  • Oxidative Stress / drug effects
  • Phosphorylation
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • Receptor, TIE-2 / metabolism
  • Ribosomal Protein S6 Kinases, 90-kDa / antagonists & inhibitors
  • Ribosomal Protein S6 Kinases, 90-kDa / genetics
  • Ribosomal Protein S6 Kinases, 90-kDa / metabolism*
  • Survivin
  • Transfection
  • Up-Regulation

Substances

  • Angiopoietin-2
  • Antibiotics, Antineoplastic
  • BIRC5 protein, human
  • CREB1 protein, human
  • Cyclic AMP Response Element-Binding Protein
  • Histones
  • Inhibitor of Apoptosis Proteins
  • Protein Kinase Inhibitors
  • Survivin
  • Doxorubicin
  • Receptor, TIE-2
  • Ribosomal Protein S6 Kinases, 90-kDa
  • mitogen and stress-activated protein kinase 1
  • APEX1 protein, human
  • DNA-(Apurinic or Apyrimidinic Site) Lyase