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

Small molecule inhibition of the CBFβ/RUNX interaction decreases ovarian cancer growth and migration through alterations in genes related to epithelial-to-mesenchymal transition.

Author information

1
Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, VA 22908, USA; Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
2
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA.
3
Department of Obstetrics and Gynecology, University of Virginia, Charlottesville, VA 22908, USA.
4
Department of Biochemistry and Molecular Genetics and Center for Cell Signaling, University of Virginia, Charlottesville, VA 22908, USA.
5
Department of Pharmaceutical Chemistry, University of Kansas, Lawrence, KS 66045, USA.
6
Department of Molecular Physiology and Biological Physics, University of Virginia, Charlottesville, VA 22908, USA. Electronic address: jhb4v@virginia.edu.

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.

PMID:
29551565
PMCID:
PMC5915923
[Available on 2019-05-01]
DOI:
10.1016/j.ygyno.2018.03.005
[Indexed for MEDLINE]

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