Oxibendazole induces apoptotic cell death in proliferating porcine trophectoderm and uterine luminal epithelial cells via mitochondria-mediated calcium disruption and breakdown of mitochondrial membrane potential

Hahyun Park, Whasun Lim, Seungkwon You, Gwonhwa Song

Research output: Contribution to journalArticle

1 Citation (Scopus)

Abstract

The well-known and effective anthelmintic oxibendazole was recently shown to have a broad spectrum of biological abilities, such as anti-cancer and anti-inflammation activities. In contrast, the mechanism of oxibendazole's anti-proliferative effect via cell signaling pathways and its role in pre-implantation has not been studied. Therefore, in this study we demonstrated the effects of oxibendazole on the proliferation of porcine trophectoderm (pTr) cells and porcine luminal epithelial (pLE) cells, a well-known in vitro model system of the fetal-maternal interface. Cell proliferation decreased in both pTr and pLE cells in response to oxibendazole, and we determined that this was modulated through intracellular cell signal transduction. Phosphorylation of ERK1/2, P90RSK, and S6 were downregulated by exposure to a 200 nM dose of oxibendazole in both types of cells, while the expression of phosphorylated JNK, AKT, and P70S6K was upregulated. Pre-treatment with a PI3K/AKT inhibitor (Wortmannin), ERK1/2 inhibitor (U0126), and JNK inhibitor (SP600125) induced the signaling interactions of these molecules, and oxibendazole co-treatment with each inhibitor resulted in even greater decreases in cell proliferation. Furthermore, intracellular and mitochondrial calcium ion accumulation was observed, which would mean that calcium ion homeostasis was disrupted, causing damage to the mitochondrial membrane potential. These deteriorated conditions ultimately led to apoptotic cell death. Taken together, the results of the present study identified that the apoptotic effect of oxibendazole on pTr and pLE cells is regulated by cell signaling pathways, and thus oxibendazole could influence the connection between the conceptus and the maternal uterus.

Original languageEnglish
Pages (from-to)9-19
Number of pages11
JournalComparative Biochemistry and Physiology Part - C: Toxicology and Pharmacology
Volume220
DOIs
Publication statusPublished - 2019 Jun 1

Keywords

  • Apoptosis
  • Cell signaling pathway
  • Oxibendazole
  • Pre-implantation

ASJC Scopus subject areas

  • Biochemistry
  • Physiology
  • Toxicology
  • Cell Biology
  • Health, Toxicology and Mutagenesis

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