Chemokine receptor CXCR4 enhances proliferation in pancreatic cancer cells through AKT and ERK dependent pathways.
OBJECTIVE
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.
Shen
Xiaoming
X
City of Hope Comprehensive Cancer Center, City of Hope, Duarte, CA, USA.
Artinyan
Avo
A
Jackson
Desmond
D
Thomas
Ryan M
RM
Lowy
Andrew M
AM
Kim
Joseph
J
D000818:Animals; D002070:Butadienes / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D054377:Chemokine CXCL12 / Q000494:pharmacology; D002867:Chromones / Q000494:pharmacology; D004791:Enzyme Inhibitors / Q000494:pharmacology; D048049:Extracellular Signal-Regulated MAP Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D019950:Mitogen-Activated Protein Kinase 1 / Q000037:antagonists & inhibitors / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000037:antagonists & inhibitors / Q000378:metabolism; D009025:Morpholines / Q000494:pharmacology; D009570:Nitriles / Q000494:pharmacology; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism*; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects
D002070:Butadienes; D054377:Chemokine CXCL12; D002867:Chromones; D004791:Enzyme Inhibitors; D048049:Extracellular Signal-Regulated MAP Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D009025:Morpholines; D009570:Nitriles; D019869:Phosphatidylinositol 3-Kinases; D000081082:Phosphoinositide-3 Kinase Inhibitors; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; C113580:U 0126; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one