title: 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.
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Ning
authors.initials: N
authors.lastname: Zheng
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Jiahang
authors.initials: J
authors.lastname: Chen
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Tao
authors.initials: T
authors.lastname: Li
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Weiqun
authors.initials: W
authors.lastname: Liu
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Liu
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Hongning
authors.initials: H
authors.lastname: Chen
authors.affiliation: Fujian Key Laboratory for Translational Research in Cancer and Neurodegenerative Diseases, Institute forTranslational Medicine, Fujian Medical University, Fuzhou, China.
authors.forename: Jichuang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Cancer Metastasis Alert and Prevention Center, and Biopharmaceutical Photocatalysis of State Key Laboratory of Photocatalysis on Energy and Environment, Fuzhou University, Fuzhou, China.|Fujian Provincial Key Laboratory of Cancer Metastasis Chemoprevention and Chemotherapy, Fuzhou University, Fuzhou, Fujian, China.
authors.forename: Lee
authors.identifier: 0000-0001-6839-5545
authors.initials: L
authors.lastname: Jia
mesh_terms: D000019:Abortifacient Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D000077216:Carcinoma, Ovarian Epithelial; D002448:Cell Adhesion / Q000187:drug effects; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects; D049109:Cell Proliferation / Q000187:drug effects; D054377:Chemokine CXCL12 / Q000378:metabolism*; D018890:Chemoprevention; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D015735:Mifepristone / Q000031:analogs & derivatives* / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D009361:Neoplasm Invasiveness / Q000473:pathology / Q000517:prevention & control*; D009375:Neoplasms, Glandular and Epithelial / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D010053:Ovary / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D010534:Peritoneal Neoplasms / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control* / Q000556:secondary*; D010537:Peritoneum / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
chemical_list: D000019:Abortifacient Agents; D000970:Antineoplastic Agents; C515255:CXCL12 protein, human; C527276:CXCR4 protein, human; D054377:Chemokine CXCL12; D019718:Receptors, CXCR4; D015735:Mifepristone; C000592521:metapristone
keywords: cancer metastasis; metapristone; mifepristone (RU486); ovarian cancer; the CXCL12/CXCR4 chemokine axis