PI3Kp110-, Src-, FAK-dependent and DOCK2-independent migration and invasion of CXCL13-stimulated prostate cancer cells

Christelle P El Haibi,Paul R Johnson,Jill Suttles,James W Lillard,Rajesh Singh,Shailesh Singh,Praveen K Sharma

doi:10.1186/1476-4598-9-85

Abstract

BackgroundMost prostate cancer (PCa)-related deaths are due to metastasis, which is mediated in part by chemokine receptor and corresponding ligand interaction. We have previously shown that PCa tissue and cell lines express high levels of the chemokine receptor CXCR5, than compared to their normal counterparts, and interaction of CXCR5 with its specific ligand (CXCL13) promoted PCa cell invasion, migration, and differential matrix metalloproteinase (MMP) expression. This study dissects some of the molecular mechanisms following CXCL13-CXCR5 interaction that mediate PCa cell migration and invasion.ResultsUsing Western blot analysis, kinase-specific cell-based ELISAs, and migration and invasion assays, we show that PCa cell lines differentially express phosphoinositide-3 kinase (PI3K) catalytic subunit isoforms and dedicator of cytokinesis 2 (DOCK2). Specifically, we show that PC3 and normal prostatic epithelial (RWPE-1), but not LNCaP cell lines expressed DOCK2, while RWPE, PC3, and LNCaP cell lines expressed PI3K-p110α and -p110β. Moreover, PC3 selectively expressed PI3K-p110γ, but LNCaP and RWPE cell lines expressed PI3Kp110δ. CXCL13 caused CXCR5-dependent activation of the PI3Kp85α in LNCaP cells, and p85α as well as -p101 in PC3 cells. CXCL13-CXCR5 interaction regulated LNCaP and PC3 cell migration and invasion through extracellular signal-regulated kinase 1/2 (ERK1/2) activation that was primarily dependent on the PI3Kp110 isoform(s), Src, and focal adhesion kinase (FAK), but not DOCK2.ConclusionsWhile additional studies will be needed to determine the PI3K-independent (i.e., DOCK2-mediated) and -dependent events that dictate PCa cell responsiveness to CXCL13, these data provide evidence of the existence of cell type- and stimulus-specific signaling events that support migration and invasion of PCa cells.

Highlights

Most prostate cancer (PCa)-related deaths are due to metastasis, which is mediated in part by chemokine receptor and corresponding ligand interaction
We demonstrated that CXCR5-bearing PCa cell lines selectively express certain matrix metalloproteinase (MMP) in response to CXCL13 [16,17,18]
Since CXCR5 is expressed by PCa cells but not by normal prostate cells, our findings suggest that CXCL13-CXCR5 interaction regulate extracellular signal-regulated kinase 1/2 (ERK1/2) phosphorylation in PCa (LNCaP and PC3) cells, but not in normal prostatic epithelial (RWPE) cells

Summary

Introduction

Most prostate cancer (PCa)-related deaths are due to metastasis, which is mediated in part by chemokine receptor and corresponding ligand interaction. We have previously shown that PCa tissue and cell lines express high levels of the chemokine receptor CXCR5, than compared to their normal counterparts, and interaction of CXCR5 with its specific ligand (CXCL13) promoted PCa cell invasion, migration, and differential matrix metalloproteinase (MMP) expression. This study dissects some of the molecular mechanisms following CXCL13-CXCR5 interaction that mediate PCa cell migration and invasion. Patients with advanced PCa initially respond to hormone therapy to decrease testosterone levels, but often develop refractive tumors. We have recently shown that prostate carcinomas differentially express CXCR5 and its expression positively correlates with stage and grade [16]. The CXCR5 gene is expressed in Burkitt's lymphoma and lymphatic tissue and plays an essential role in B cell migra-

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