Abstract
SDF-1/CXCR4 signaling axis determines the proliferative potential and site-specific cancer metastasis. Recent studies suggest involvement of the axis and steroidal hormone in ovarian cancer metastasis. Here we hypothesize that mifepristone (RU486), a well-known progesterone-based abortifacient, might interfere this axis and inhibit ovarian cancer metastasis. Mifepristone at concentrations < IC50 inhibited expression of CXCR4 on cell surface of ovarian cancer SKOV-3 and IGROV-1, and reduced expression of the intracellular CXCR4 protein and its related mRNA activated by SDF-1. SDF-1 significantly stimulated proliferation of SKOV-3 and IGROV-1 cells with concomitant increases in intracellular phosphorylation of Akt and ERK. SDF-1 activated cell chemotatic migration and actin polymerization, and up-regulated expression of MMP-2, MMP-9, COX-2, VEGF without influencing the adhesion molecules ICAM-1 and integrins β1, α1, α3, α5, and α6. The above-mentioned effects of SDF-1 could be antagonized by mifepristone concentration-dependently, and CXCR4 antagonist AMD3100. Mifepristone suppressed the SDF-1-induced migration, invasion and adhesion of the cancer cells to extracellular matrixes. Three-day pretreatment of nude mice with mifepristone (5 and 20 mg/kg/day) followed by a single intraperitoneal IGROV-1 inoculation, along with repeated SDF-1 and mifepristone administrations in turn every other day for 36 days significantly reduced ascitic fluid, metastatic foci, tumor weight and immunoreactivity of CXCR4 in comparison with the SDF-1-treated control. Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis.
Highlights
With an overall survival rate of less than 30%, ovarian cancer remains a poorly addressed health problem relative to other generally diagnosed gynecologic malignancies
Our results suggest that mifepristone inhibit SDF-1/CXCR4 signaling axis, may have preventive and therapeutic effects on ovarian cancer metastasis
As CXCR4 was activated by SDF-1, we found no change in CXCR4 expression at the levels of mRNA and total protein (Figure 1C and 1E), but SDF-1 itself was able to produce a significant decline of CXCR4 expression on the cell surface (Figure 1D)
Summary
With an overall survival rate of less than 30%, ovarian cancer remains a poorly addressed health problem relative to other generally diagnosed gynecologic malignancies. Chemokines binding to corresponding specific chemokine www.impactjournals.com/oncotarget receptors induce leukocyte infiltration, regulate immune functions, conduct the homing of carcinomas cells to specific metastatic sites, and mediate angiogenesis at the tumor microenvironment [2]. Dysregulated expression of the chemokine ligand SDF-1 (stromal derived factor-1, or CXCL12), or its cognate receptor CXCR4 (C-X-C chemokine receptor type 4), is associated with higher grades and poorer prognosis in various human cancers, including ovarian carcinomas [3]. Targeted metastasis of cancer cells with elevated expression of CXCR4 to specific sites guided by the high level of SDF-1 suggests a new therapeutic strategy to interrupt the SDF-1/CXCR4 axis and inhibit cancer metastasis [4]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
