Chemokine Receptor CXCR4 Enhances Proliferation in Pancreatic Cancer Cells Through AKT and ERK Dependent Pathways

Objectives: We previously detected CXCR4 expression in pancreatic intraepithelial neoplasia (PanIN) tissues and demonstrated CXCR4-enhanced proliferation of PanIN cells. Our objective was to determine if the CXCR4 targets AKT and ERK mediate CXCR4-dependent PanIN and pancreatic cancer proliferation. Methods: We exposed cultured murine-derived PanIN, invasive pancreatic cancer (5143PDA) and liver metastasis (5143LM) cells, and human pancreatic cancer PANC-1 cells to CXCL12, the specific CXCR4 ligand, and measured phosphorylation of AKT and ERK1/2. The roles of AKT and ERK1/2 in CXCR4-dependent cell proliferation were assessed by the PI/3K-AKT small molecular inhibitor LY294002 and the ERK signaling inhibitor UO126. Results: We discovered increases in phosphorylation of AKT in PanIN, 5143PDA, and PANC-1 cells but no increase in 5143LM cells after exposure to CXCL12. We also observed that exposure to CXCL12 over varying periods phosphorylated ERK1/2 in an oscillatory pattern for all cell lines. Administration of LY294002 resulted in complete abrogation of CXCL12-induced proliferation in PanIN, 5143LM, and PANC-1 cells but not 5143PDA cells, whereas UO126 resulted in complete abrogation of CXCR4-enhanced proliferation in all cell lines. Conclusions: Our studies show that CXCR4-induced proliferation is mediated by both AKT and ERK signaling in both murine and human pancreatic cancer cells.