Inhibition of KIF20A by BKS0349 reduces endometriotic lesions in a xenograft mouse model

Mol Hum Reprod. 2019 Sep 1;25(9):562-571. doi: 10.1093/molehr/gaz044.

Abstract

Several studies have suggested a possible etiological association between ovarian endometriosis and ovarian cancer. Evidence has shown that KIF20A overexpression might confer a malignant phenotype to ovarian tumors by promoting proliferation and inhibiting apoptosis. However, no data about the role of KIF20A in endometriosis have been described. In this study, the human endometrium (n = 4) was transfected by mCherry adenovirus and intraperitoneally implanted in mice. Subsequently, mice were divided in three groups (n = 8/group) that were treated with Vehicle, BKS0349 (KIF20A-antagonist) or cabergoline (dopamine receptor agonist) for 21 days. mCherry-labeled endometriotic lesions were monitored over time using the IVIS Imaging System. Mice were sacrificed 72 h after the last administration; proliferation was evaluated by immunohistochemistry and apoptosis by TUNEL. CCND1 gene expression (G1 phase-related gene) was measured by qRT-PCR. A significant reduction in mCherry-fluorescent signal was observed in the BKS0349 group after treatment ended (D24) compared with D0 (P-value = 0.0313). Moreover, the mCherry signal on D24 showed a significant decrease in the BKS0349 group compared with controls (P-value = 0.0303), along with significant size reduction of endometriotic lesions observed in the BKS0349 group compared with control on D24 (P-value = 0.0006). Functional studies showed a significant reduction in proliferating cells in the BKS0349-treated group compared with controls (P-value = 0.0082). In addition, CCND1 expression was decreased in the BKS0349 group compared with control (P-value = 0.049) at D24 and a significant increase in apoptotic cells among endometriotic lesions in BKS0349-treated mice was observed compared with control (P-value = 0.0317). Based on these findings, we concluded that BKS0349 induces apoptosis and inhibits cell proliferation, reducing endometriotic lesion size and suggesting KIF20A inhibition by BKS0349 as a novel therapeutic treatment for endometriosis.

Keywords: KIF20A; apoptosis; cell cycle; cell proliferation; endometriosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects
  • Cabergoline / pharmacology
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • Endometriosis / diagnosis
  • Endometriosis / pathology
  • Endometriosis / prevention & control*
  • Endometrium / drug effects
  • Endometrium / pathology
  • Endometrium / transplantation
  • Female
  • Heterografts
  • Humans
  • Kinesin / antagonists & inhibitors*
  • Mice
  • Mice, Nude
  • Optical Imaging
  • Peritoneal Diseases / diagnosis
  • Peritoneal Diseases / pathology
  • Peritoneal Diseases / prevention & control*

Substances

  • KIF20A protein, human
  • Kinesin
  • Cabergoline