Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention

Abstract

Recent global epidemiological studies revealed the lower ovarian cancer death from long-term use of oral contraceptives. However, the underlying mechanism of action is not clear. Here, we use the abortifacient metapristone (RU486 derivative) to test the hypothesis that the contraceptives might interrupt CXCL12/CXCR4 chemokine axis to inhibit ovarian cancer metastasis. Metapristone at concentrations (<IC50) remarkably reduces CXCL12-induced CXCR4 expression on ovarian SKOV-3 and IGROV-1 cell lines, and down-regulates the CXCR4-related mRNAs and intracellular proteins. Metapristone concentration-dependently inhibits cancer cell proliferation via interfering the CXCL12-activated Akt and ERK signaling pathways. The effect of CXCL12 could be antagonized by AMD3100. Metapristone interrupts the cellular filamentous actin polymerization and the related chemotaxis. Metapristone also concentration-dependently inhibits the events of cellular invasion, migration, and adhesion. The inhibition is related to down-regulation of the invasive molecules MMP-2, MMP-9, COX-2, and VEGF without affecting the adhesion molecules ICAM-1, integrins α1, α3, α5, α6, and β1. Six-week in vivo xenograft study confirms the anti-metastatic effect of metapristone on mouse ascites and metastatic foci induced by intraperitoneal IGROV-1 and CXCL12. The present studies, for the first time, reveal the therapeutic effect of metapristone on ovarian metastasis and the CXCL12/CXCR4 axis-related mechanisms of actions.

CXCR7 is not obligatory for CXCL12‐CXCR4‐induced epithelial‐mesenchymal transition in human ovarian cancer

“…CXCL12‐CXCR4 axis is strongly linked to intraperitoneal dissemination of ovarian cancer . Our group and others have corroborated that the CXCL12‐CXCR4 chemokine axis plays a critical role in ovarian cancer metastasis through mediating a variety of cellular functions such as cell proliferation, migration, invasion, and adhesion . As one of the major chemokine receptors, CXCR4 has been demonstrated to be aberrantly expressed in a variety of human cancers, including ovarian cancer, but its expression is low or absent in many normal tissues, including ovary .…”

“…Filamentous actin (F‐actin) staining was performed as we described previously . Briefly, the cells were fixed using 4.0% (v/v) paraformaldehyde on 35‐mm glass‐bottom culture dishes, permeabilized with 0.1% (v/v) Triton X‐100, and blocked with 0.1% (w/v) bovine serum albumin (BSA) in phosphate buffered solution (PBS).…”

“…The cell chemotaxis assay was performed in transwell inserts (Corning Costar, Cambridge, MA) as described previously. 12 Briefly, the cells were trypsinized, washed, and added to the upper chamber at a density of 1.5 × 10 5 per well, with increasing concentration of CXCL12 (Sino Biological Inc., Beijing, China) placed to the lower chamber in serumfree media as a chemo-attractant followed by incubation for 24 and 48 h, respectively. For the competitive chemotaxis assay, CXCL12 (0, 10, 50, and 100 ng/mL) was mixed with cells (1.5 × 10 5…”

“…9 Our group and others have corroborated that the CXCL12-CXCR4 chemokine axis plays a critical role in ovarian cancer metastasis through mediating a variety of cellular functions such as cell proliferation, migration, invasion, and adhesion. [9][10][11][12][13] As one of the major chemokine receptors, CXCR4 has been demonstrated to be aberrantly expressed in a variety of human cancers, including ovarian cancer, but its expression is low or absent in many normal tissues, including ovary. 6 Therefore, CXCR4 expression is closely related to malignization and poor prognosis for ovarian cancer patients in the clinic.…”

Downregulation of KCTD12 contributes to melanoma stemness by modulating CD271

“…Immunofluorescence assays were conducted as previously reported 33 . Briefly, cells plated on coverslips were fixed with 4% paraformaldehyde for 30 min.…”