Abortifacient metapristone (RU486 derivative) interrupts CXCL12/CXCR4 axis for ovarian metastatic chemoprevention. Issue 8 (30th March 2017)

• Record Type: Journal Article
• Authors: Zheng, Ning; Chen, Jiahang; Li, Tao; Liu, Weiqun; Liu, Jian; Chen, Hongning; Wang, Jichuang; Jia, Lee
• Is Part Of: Molecular carcinogenesis. Volume 56:Issue 8(2017)
• Page Start: 1896
• Page End: 1908
• Publication Date: 2017-03-30
• Subjects: cancer metastasis -- metapristone -- mifepristone (RU486) -- ovarian cancer -- the CXCL12/CXCR4 chemokine axis; Carcinogenesis -- Molecular aspects -- Periodicals; 616.994071
• DOI: 10.1002/mc.22645
• Languages: English
• ISSNs: 0899-1987

Abstract

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.