Zheng Ning, Chen Jiahang, Li Tao, Liu Weiqun, Liu Jian, Chen Hongning, Wang Jichuang, Jia Lee
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.
Mol Carcinog. 2017 Aug;56(8):1896-1908. doi: 10.1002/mc.22645. Epub 2017 Mar 30.
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.
近期全球流行病学研究显示，长期使用口服避孕药可降低卵巢癌死亡率。然而，其潜在作用机制尚不清楚。在此，我们使用堕胎药米非司酮（RU486衍生物）来验证以下假说：避孕药可能通过干扰CXCL12/CXCR4趋化因子轴来抑制卵巢癌转移。米非司酮在低于半数抑制浓度（<IC50）时，可显著降低CXCL12诱导的卵巢SKOV-3和IGROV-1细胞系上CXCR4的表达，并下调与CXCR4相关的mRNA和细胞内蛋白。米非司酮通过干扰CXCL12激活的Akt和ERK信号通路，呈浓度依赖性地抑制癌细胞增殖。AMD3100可拮抗CXCL12的作用。米非司酮可干扰细胞丝状肌动蛋白聚合及相关趋化作用。米非司酮还呈浓度依赖性地抑制细胞侵袭、迁移和黏附事件。这种抑制作用与侵袭分子MMP-2、MMP-9、COX-2和VEGF的下调有关，而不影响黏附分子ICAM-1、整合素α1、α3、α5、α6和β1。为期六周的体内异种移植研究证实了米非司酮对腹腔注射IGROV-1和CXCL12诱导的小鼠腹水和转移灶具有抗转移作用。本研究首次揭示了米非司酮对卵巢癌转移的治疗作用以及与CXCL12/CXCR4轴相关的作用机制。
