Up-regulation of CXCR4 Expression in PC-3 Cells by Stromal-Derived Factor-1α (CXCL12) Increases Endothelial Adhesion and Transendothelial Migration: Role of MEK/ERK Signaling Pathway–Dependent NF-κB Activation
Open Access
- 1 November 2005
- journal article
- Published by American Association for Cancer Research (AACR) in Cancer Research
- Vol. 65 (21), 9891-9898
- https://doi.org/10.1158/0008-5472.can-05-1293
Abstract
The chemokine stromal-derived factor-1α (SDF-1α/CXCL-12) and its receptor, CXCR4, play a crucial role in adhesion and transendothelium migration (TEM) of prostate cancer cells. We tested the hypothesis that enhanced expression of CXCR4 in prostate cancer cells is dependent upon SDF-1α-mediated activation of nuclear factor-κB (NF-κB). SDF-1α increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1α enhanced the NF-κB-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1α increased PC-3 cell adhesion to the human umbilical vein endothelial cell monolayer and enhanced TEM, which was abrogated with anti-CXCR4 monoclonal antibody (mAb). Suppression of NF-κB activity in PC-3 cells by a mutant IκBα super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM. Transient overexpression of p65 subunit of NF-κB in PC-3 cells up-regulated CXCR4 receptor expression and increased the adhesion and TEM of these cells in response to SDF-1α gradient. Treatment of PC-3 cells with SDF-1α leads to nuclear translocation of NF-κB protein within 15 to 30 minutes, which correlated with IκBα phosphorylation. A p42/44 mitogen-activated protein kinase [MAPK, extracellular signal regulated kinase-1/2 (ERK-1/2)] biphasic activation pattern was observed in these cells at 15 minutes and 3 hours after SDF-1α treatment. Phosphorylation of IκB kinase α was observed within 30 minutes, which was blocked by PD98059 [MAPK kinase (MEK) inhibitor]. PD98059 cotreatment significantly inhibited SDF-1α-induced NF-κB reporter activity and CXCR4 receptor expression as shown by flow cytometry. These data suggest that SDF-1α-induced expression of CXCR4 in PC-3 cells is dependent on MEK/ERK signaling cascade and NF-κB activation.Keywords
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