NF-κB inhibition in human hepatocellular carcinoma and its potential as adjunct to sorafenib based therapy

Jian Min Wu, Hongmiao Sheng, Romil Saxena, Nicholas James Skill, Poornima Bhat-Nakshatri, Menggang Yu, Harikrishna Nakshatri, Mary A. Maluccio

Research output: Contribution to journalArticle

54 Scopus citations

Abstract

Nuclear factor-kappaB (NF-κB) has been shown to play an important role in the development and progression of cancer. In this study, we systematically examined NF-κBp65 signaling pathway in both human hepatocellular carcinoma (HCC) tissue and HCC cell lines. NF-κBp65 signaling pathway is aberrantly expressed and activated in both human HCC tissue and HCC Hep3B cells. Inhibition of NF-κB activity significantly reduced proliferation and invasion of Hep3B cells as well as down-regulated the expression of invasion-related molecules including matrix metalloproteinase (MMP)-2, MMP-9, membrane type-1 MMP (MT1-MMP), urokinase plasminogen activator (uPA) and vascular endothelial growth factor (VEGF). Hep3B cells exhibited a dose-dependent increase in apoptosis after receiving sorafenib treatment. Inhibition of NF-κB activity strongly sensitized Hep3B cells to sorafenib-induced cell death. Mechanistically, combined treatment of sorafenib and NF-κB inhibition enhanced inhibition of MAPK signaling and down-regulation of anti-apoptotic protein Mcl-1 expression. These observations indicate that inhibition of NF-κB may be a potential antineoplastic therapy for HCC, especially the combination of NF-κB inhibition and sorafenib provides a novel therapeutic strategy for patients with advanced-stage HCC.

Original languageEnglish (US)
Pages (from-to)145-155
Number of pages11
JournalCancer Letters
Volume278
Issue number2
DOIs
StatePublished - Jun 18 2009

Keywords

  • Hepatocellular carcinoma (HCC)
  • NF-κB
  • Sorafenib
  • Therapy

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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