Regulation of Inflammation by the NF-κB Pathway in Ovarian Cancer Stem Cells

Am J Reprod Immunol. 2011 Apr;65(4):438-47. doi: 10.1111/j.1600-0897.2010.00914.x. Epub 2010 Sep 6.

Abstract

Problem: The NFκB pathway is a major source of pro-inflammatory cytokines, which may contribute to cancer chemoresistance. We showed that constitutive NFκB activity is characteristic of the ovarian cancer stem cells (OCSCs). The aim of this study is to determine whether the inhibition of NFκB by Eriocalyxin B (EriB) in the OCSCs may induce cell death in otherwise chemoresistant cells.

Methods: OCSCs and mature ovarian cancer cells (mOCCs) were treated with increasing concentrations of EriB. Cell viability was measured using the Celltiter 96 assay, and caspase activity was quantified using Caspase-Glo™ assay. Cytokine levels were quantified using xMAP technology.

Results: EriB decreased the percent of viable cells in all cultures tested with GI(50) of 0.5-1 μm after 48 hrs of treatment. The intracellular changes associated with EriB-induced cell death are: (i) inhibition of NF-κB activity; (ii) decreased cytokine production; (iii) activation of caspases; and (iv) down-regulation of XIAP. In addition, EriB is able to sensitize OCSCs to TNFα and FasL-mediated cell death.

Conclusion: Inhibition of the NFκB pathway induces cell death in the OCSCs. Because the OCSCs may represent the source of recurrence and chemoresistance, the use of NFκB inhibitors like EriB may prevent recurrence in patients with ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis / drug effects
  • Blotting, Western
  • Caspases / metabolism
  • Cell Survival / drug effects
  • Cells, Cultured
  • Cytokines / biosynthesis
  • Diterpenes / pharmacology*
  • Electrophoresis, Polyacrylamide Gel
  • Female
  • Humans
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / metabolism*
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / immunology*
  • Neoplastic Stem Cells / metabolism*
  • Ovarian Neoplasms / immunology
  • Ovarian Neoplasms / metabolism*
  • Ovarian Neoplasms / pathology
  • Tumor Necrosis Factor-alpha / antagonists & inhibitors
  • X-Linked Inhibitor of Apoptosis Protein / genetics

Substances

  • Cytokines
  • Diterpenes
  • NF-kappa B
  • Tumor Necrosis Factor-alpha
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • eriocalyxin B
  • Caspases