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Up-regulation of CXCR4 Expression in PC-3 Cells by Stromal-Derived Factor-1 (CXCL12) Increases Endothelial Adhesion and Transendothelial Migration: Role of MEK/ERK Signaling Pathway–Dependent NF-B Activation

Departments of ¹ Pharmacology and ² Urology, Tulane University Health Sciences Center, New Orleans, Louisiana

Requests for reprints: Krishna C. Agrawal, Department of Pharmacology, SL-83, Tulane University Health Sciences Center, New Orleans, LA 70112. Phone: 504-988-5444; Fax: 504-988-5283; E-mail: agrawal{at}tulane.edu.

The chemokine stromal-derived factor-1 (SDF-1/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-1-mediated activation of nuclear factor-B (NF-B). SDF-1 increased the CXCR4 mRNA and protein expression in PC-3 cells but not in LNCaP cells. Similarly, SDF-1 enhanced the NF-B-dependent transcriptional activity in PC-3 cells but not in LNCaP cells. SDF-1 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-B activity in PC-3 cells by a mutant IB super-repressor adenoviral vector decreased the CXCR4 mRNA expression and inhibited adhesion and TEM. Transient overexpression of p65 subunit of NF-B in PC-3 cells up-regulated CXCR4 receptor expression and increased the adhesion and TEM of these cells in response to SDF-1 gradient. Treatment of PC-3 cells with SDF-1 leads to nuclear translocation of NF-B protein within 15 to 30 minutes, which correlated with IB 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-1 treatment. Phosphorylation of IB kinase was observed within 30 minutes, which was blocked by PD98059 [MAPK kinase (MEK) inhibitor]. PD98059 cotreatment significantly inhibited SDF-1-induced NF-B reporter activity and CXCR4 receptor expression as shown by flow cytometry. These data suggest that SDF-1-induced expression of CXCR4 in PC-3 cells is dependent on MEK/ERK signaling cascade and NF-B activation.

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