Stromal cell-derived factor 1alpha stimulates human glioblastoma cell growth through the activation of both extracellular signal-regulated kinases 1/2 and Akt.
In this paper, we describe the role of chemokine receptor CXCR4 activation by its natural ligand, the chemokine stromal cell-derived factor (SDF-1) (CXCL12), in glioblastoma cell growth in vitro. We show that both CXC chemokine receptor 4 (CXCR4) and SDF-1 mRNA are expressed in several human glioblastoma multiforme tumor tissues and in two human glioblastoma cell lines, U87-MG and DBTRG-05MG. These cells are able to secrete SDF-1 under basal conditions, and the rate of secretion is highly increased after lipopolysaccharide or 1% fetal bovine serum treatment. Exogenous SDF-1alpha induces proliferation in a dose-dependent manner in both cell lines. Moreover, we observed that SDF-1alpha-dependent proliferation is correlated with phosphorylation and activation of both extracellular signal-regulated kinases 1/2 and Akt and that these kinases are independently involved in glioblastoma cell proliferation. The role of CXCR4 stimulation in glioblastoma cell growth is further demonstrated by the ability of human monoclonal CXCR4 antibody (clone 12G5) to inhibit the SDF-1alpha-induced proliferation as well as the proliferation induced by SDF-1-releasing treatments (lipopolysaccharide and 1% fetal bovine serum). These data support a role for SDF-1alpha in the regulation of glioblastoma growth in vitro, likely through an autocrine/paracrine mechanism.
Barbero
Simone
S
Pharmacology and Neuroscience, National Institute for Cancer Research c/o Advanced Biotechnology Center, Genoa, Italy.
Bonavia
Rudy
R
Bajetto
Adriana
A
Porcile
Carola
C
Pirani
Paolo
P
Ravetti
Jean Louis
JL
Zona
Gian Luigi
GL
Spaziante
Renato
R
Florio
Tullio
T
Schettini
Gennaro
G
D000818:Animals; D002455:Cell Division / Q000502:physiology; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D004273:DNA, Neoplasm / Q000096:biosynthesis; D004789:Enzyme Activation; D005909:Glioblastoma / Q000201:enzymology / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D020935:MAP Kinase Signaling System; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism*; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism*; D010766:Phosphorylation; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D051381:Rats; D019718:Receptors, CXCR4 / Q000096:biosynthesis / Q000378:metabolism / Q000502:physiology*; D014407:Tumor Cells, Cultured
C515255:CXCL12 protein, human; D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D004273:DNA, Neoplasm; D011518:Proto-Oncogene Proteins; D019718:Receptors, CXCR4; C494918:AKT1 protein, human; C494920:Akt1 protein, rat; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases