Proteasome inhibition by bortezomib decreases proliferation and increases apoptosis in ovarian granulosa cell tumors

Reprod Sci. 2009 Apr;16(4):397-407. doi: 10.1177/1933719108327589. Epub 2008 Dec 15.

Abstract

Granulosa cell tumors of the ovary represent approximately 5% of malignant ovarian tumors. The molecular pathogenesis of granulosa cell tumors is not known but 2 human granulosa cell tumor-derived cell lines, COV434 and KGN, exhibit constitutive activation of the nuclear factor kappa-B (NFkappaB)-signaling pathway. The proteasomal inhibitor, bortezomib, has a complex mode of action which includes inhibition of NFkappaB signaling. We examined the effect of bortezomib on the COV434 and KGN cells. The COV434 and KGN cells both showed a dose-dependent inhibition of cell proliferation and viability in response to bortezomib together with an increase in apoptosis. This was achieved at concentrations within the range seen for clinically responsive tumors. The NFkappaB constitutive activity was not however decreased. Genes were identified that were regulated in both lines in response to bortezomib. This study suggests that advanced granulosa cell tumors, as represented by the cell lines, may respond to bortezomib either alone or in combination with other agents.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacology
  • Apoptosis / drug effects*
  • Boronic Acids / pharmacology*
  • Bortezomib
  • Cell Division / drug effects
  • Cell Line, Tumor
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • Female
  • Gene Expression
  • Granulosa Cell Tumor / pathology*
  • Humans
  • NF-kappa B / antagonists & inhibitors
  • NF-kappa B / genetics
  • Oligonucleotide Array Sequence Analysis
  • Ovarian Neoplasms / pathology*
  • Protease Inhibitors / pharmacology*
  • Proteasome Inhibitors*
  • Pyrazines / pharmacology*
  • Reverse Transcriptase Polymerase Chain Reaction
  • Transfection
  • X-Linked Inhibitor of Apoptosis Protein / genetics

Substances

  • Antineoplastic Agents
  • Boronic Acids
  • NF-kappa B
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Pyrazines
  • X-Linked Inhibitor of Apoptosis Protein
  • XIAP protein, human
  • Bortezomib