Small Molecule Inhibition of the CBFβ/RUNX Interaction Decreases Ovarian Cancer Growth and Migration Through Alterations in Genes Related to Epithelial-To-Mesenchymal Transition

Gynecol Oncol. 2018 May;149(2):350-360. doi: 10.1016/j.ygyno.2018.03.005. Epub 2018 Mar 16.

Abstract

Objective: Ovarian cancer survival and treatment have improved minimally in the past 20years. Novel treatment strategies are needed to combat this disease. This study investigates the effects of chemical inhibition of the CBFβ/RUNX protein-protein interaction on ovarian cancer cell lines.

Methods: Ovarian cancer cell lines were treated with CBFβ/RUNX inhibitors, and the effects on proliferation, DNA replication, wound healing, and anchorage-independent growth were measured. RNA-Seq was performed on compound-treated cells to identify differentially expressed genes. Genes altered by compound treatment were targeted with siRNAs, and effects on DNA replication and wound healing were measured.

Results: Chemical inhibition of the CBFβ/RUNX interaction decreases ovarian cancer cell proliferation. Inhibitor treatment leads to an S-phase cell cycle delay, as indicated by an increased percentage of cells in S-phase, and a decreased DNA replication rate. Inhibitor treatment also reduces wound healing and anchorage-independent growth. RNA-Seq on compound-treated cells revealed changes in a small number of genes related to proliferation and epithelial-to-mesenchymal transition. siRNA-mediated knockdown of INHBA and MMP1 - two genes whose expression decreases with compound treatment - slowed DNA replication and impaired wound healing.

Conclusions: Chemical inhibition of the CBFβ/RUNX interaction is a viable strategy for the treatment of ovarian cancer.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Carcinoma, Ovarian Epithelial
  • Cell Growth Processes / drug effects
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Core Binding Factor alpha Subunits / antagonists & inhibitors*
  • Core Binding Factor alpha Subunits / metabolism
  • Epithelial-Mesenchymal Transition / genetics*
  • Female
  • Humans
  • Mice
  • Mice, Nude
  • Neoplasms, Glandular and Epithelial / drug therapy*
  • Neoplasms, Glandular and Epithelial / genetics*
  • Neoplasms, Glandular and Epithelial / metabolism
  • Neoplasms, Glandular and Epithelial / pathology
  • Ovarian Neoplasms / drug therapy*
  • Ovarian Neoplasms / genetics*
  • Ovarian Neoplasms / metabolism
  • Ovarian Neoplasms / pathology
  • Random Allocation
  • Small Molecule Libraries / pharmacology*
  • Xenograft Model Antitumor Assays

Substances

  • Core Binding Factor alpha Subunits
  • Small Molecule Libraries