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.
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 humanpancreatic 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 humanpancreatic cancer cells.
Authors: Ihsan Ekin Demir; Kristina Kujundzic; Paulo L Pfitzinger; Ömer Cemil Saricaoglu; Steffen Teller; Timo Kehl; Carmen Mota Reyes; Linda S Ertl; Zhenhua Miao; Thomas J Schall; Elke Tieftrunk; Bernhard Haller; Kalliope Nina Diakopoulos; Magdalena U Kurkowski; Marina Lesina; Achim Krüger; Hana Algül; Helmut Friess; Güralp O Ceyhan Journal: Proc Natl Acad Sci U S A Date: 2016-12-16 Impact factor: 11.205
Authors: Ajay P Singh; Sumit Arora; Arun Bhardwaj; Sanjeev K Srivastava; Madhavi P Kadakia; Bin Wang; William E Grizzle; Laurie B Owen; Seema Singh Journal: J Biol Chem Date: 2012-09-20 Impact factor: 5.157
Authors: Colin D Weekes; Dongweon Song; John Arcaroli; Lora A Wilson; Belen Rubio-Viqueira; George Cusatis; Elizabeth Garrett-Mayer; Wells A Messersmith; Robert A Winn; Manuel Hidalgo Journal: Neoplasia Date: 2012-08 Impact factor: 5.715