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Molecular mechanisms underlying mifepristone's agonistic action on ovarian cancer progression

Donata Ponikwicka-Tyszko1, Marcin Chrusciel2, Joanna Stelmaszewska3

  • 1Department of Biology and Pathology of Human Reproduction, Institute of Animal Reproduction and Food Research, Polish Academy of Sciences, Olsztyn, Poland.

Ebiomedicine
|August 31, 2019
PubMed
Abstract

Insights

Mifepristone unexpectedly promotes ovarian cancer growth by activating PGRMC1, not the progesterone receptor. Blocking PGRMC1 may offer a new ovarian cancer treatment strategy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Ovarian cancer treatments utilizing mifepristone (MF) have yielded unsuccessful clinical outcomes.
  • Despite in vitro data showing MF as a potent progesterone (P4) antagonist, its clinical efficacy in ovarian cancer remains unproven.

Purpose of the Study:

  • To investigate the molecular mechanisms behind mifepristone's (MF) agonistic effects on ovarian cancer progression.
  • To explore potential novel therapeutic strategies targeting PGRMC1 in ovarian cancer.

Main Methods:

  • Utilized human and murine ovarian cancer cell lines, including primary epithelial ovarian cancer (HG-hOEC) cells and their explants.
  • Employed in vivo transgenic mouse models of ovarian cancer to assess MF's molecular actions.
  • Investigated the role of progesterone receptor membrane component 1 (PGRMC1) in MF-induced ovarian cancer cell behaviors.

Main Results:

  • Ovarian cancer cells predominantly express PGRMC1, with minimal or no nuclear progesterone receptor (PGR).
  • Mifepristone (MF) significantly enhanced ovarian cancer cell migration, proliferation, and in vivo growth.
  • MF treatment induced PGRMC1 translocation to the nucleus, an effect reversed by a PGRMC1 inhibitor.
  • Therapeutic doses of MF resulted in low tissue concentrations, promoting ovarian cancer growth rather than exhibiting antitumor effects.

Conclusions:

  • Ovarian cancer treated with MF and P4 may exhibit adverse agonistic effects, particularly when classical nuclear PGRs are absent.
  • Blocking PGRMC1 activity presents a promising novel therapeutic avenue for ovarian cancer treatment.
  • Further research into PGRMC1-targeted therapies is warranted for ovarian cancer management.
Keywords:
MifepristoneNuclear progesterone receptorsOvarian cancerProgesteroneProgesterone receptor membrane component 1

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