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


RESULTS
Using 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-p110alpha and -p110beta. Moreover, PC3 selectively expressed PI3K-p110gamma, but LNCaP and RWPE cell lines expressed PI3Kp110delta. CXCL13 caused CXCR5-dependent activation of the PI3Kp85alpha in LNCaP cells, and p85alpha 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.


CONCLUSIONS
While 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.
El Haibi
Christelle P
CP
Department of of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA.
Sharma
Praveen K
PK
Singh
Rajesh
R
Johnson
Paul R
PR
Suttles
Jill
J
Singh
Shailesh
S
Lillard
James W
JW
D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000502:physiology; D054382:Chemokine CXCL13 / Q000378:metabolism / Q000494:pharmacology; D054365:Chemokine CXCL5 / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D004797:Enzyme-Linked Immunosorbent Assay; D051417:Focal Adhesion Kinase 1 / Q000378:metabolism*; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors / Q000378:metabolism*; D006801:Humans; D008297:Male; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D015398:Signal Transduction / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
D054382:Chemokine CXCL13; D054365:Chemokine CXCL5; D051417:Focal Adhesion Kinase 1; D020690:GTPase-Activating Proteins; D020662:Guanine Nucleotide Exchange Factors; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases; C402110:DOCK2 protein, human; C496050:PTK2 protein, human