Characterization of the CXCR4 signaling in pancreatic cancer cells.
CXCL12 and its receptor, CXCR4, are emerging as promising targets for modulating growth, angiogenesis, and metastasis in several human cancers. Indeed, blocking the receptor is sufficient to prevent metastasis and angiogenesis in experimental breast cancer xenografts. Recently, the biological effect of the CXCR4 in pancreatic cancer, one of the most deadly neoplastic diseases, has been reported. However, the molecular mechanism by which CXCR4 contributes to these properties is not completely understood. In this paper, we characterize the signaling pathways activated by CXCR4 in pancreatic cancer. We show that after CXCR4 activation, EGFR becomes tyrosine phosphorylated, and the kinase activity of this receptor, together with the activation of MMPs, Src, and PI3-Kinase, is required for CXCR4-mediated ERK activation. Analysis of this cascade in pancreatic cancer cells revealed that the ERK-mediated pathway regulates genes involved in angiogenesis, such as VEGF, CD44, HIF1alpha, and IL-8. Furthermore, ERK blockage inhibits the migration and tube formation of endothelial cells induced by CXCL12. Considering that inhibitors for several components of this pathway, including CXCR4 itself, are at different stages of clinical trials, this study provides theoretical justification for the clinical testing of these drugs in pancreatic cancer, thus extending the list of potential targets for treating this dismal disease.
Billadeau
Daniel D
DD
Oncology Research Department, Mayo Clinic College of Medicine, Rochester, MN 55905, USA.
Chatterjee
Subrha
S
Bramati
Patricia
P
Sreekumar
Raghavakaimal
R
Shah
Vijay
V
Hedin
Karen
K
Urrutia
Raul
R
D001011:Aorta / Q000166:cytology* / Q000378:metabolism; D015153:Blotting, Western; D002448:Cell Adhesion; D002465:Cell Movement / Q000502:physiology*; D049109:Cell Proliferation; D004730:Endothelium, Vascular / Q000166:cytology* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D066246:ErbB Receptors / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D018960:Hyaluronan Receptors / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D047468:Immunoprecipitation; D016209:Interleukin-8 / Q000378:metabolism; D020935:MAP Kinase Signaling System; D018919:Neovascularization, Physiologic; D020411:Oligonucleotide Array Sequence Analysis; D010190:Pancreatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D010766:Phosphorylation; D019718:Receptors, CXCR4 / Q000378:metabolism*; D015398:Signal Transduction; D014443:Tyrosine / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism
C497483:CD44 protein, human; D004791:Enzyme Inhibitors; C497442:HIF1A protein, human; D018960:Hyaluronan Receptors; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D016209:Interleukin-8; D019718:Receptors, CXCR4; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D014443:Tyrosine; D019869:Phosphatidylinositol 3-Kinases; D066246:ErbB Receptors