Akt activation, but not extracellular signal-regulated kinase activation, is required for SDF-1alpha/CXCR4-mediated migration of epitheloid carcinoma cells.
Emerging evidence shows that the stromal cell-derived factor 1 (SDF-1)/CXCR4 interaction regulates multiple cell signaling pathways and a variety of cellular functions such as cell migration, proliferation, and survival. There is little information linking the cellular functions and individual signaling pathways mediated by SDF-1 and CXCR4 in human cancer cells. In this study, we have shown that human epitheloid carcinoma HeLa cells express functional CXCR4 by reverse transcription-PCR, immunofluorescent staining, and 125I-SDF-1alpha ligand binding analyses. The treatment of HeLa cells with recombinant SDF-1alpha results in time-dependent Akt and extracellular signal-regulated kinase 1/2 (ERK1/2) activations. The SDF-1alpha-induced Akt and ERK1/2 activations are CXCR4 dependent as confirmed by their total inhibition by T134, a CXCR4-specific peptide antagonist. Cell signaling analysis with pathway-specific inhibitors reveals that SDF-1alpha-induced Akt activation is not required for ERK1/2 activation and vice versa, indicating that activations of Akt and ERK1/2 occur independently. Functional analysis shows that SDF-1alpha induces a CXCR4-dependent migration of HeLa cells. The migration can be totally blocked by phosphoinositide 3-kinase inhibitors, wortmannin or LY294002, whereas mitogen-activated protein/ERK kinase inhibitors, PD98059 and U0126, have no significant effect on SDF-1alpha-induced migration, suggesting that Akt activation, but not ERK1/2 activation, is required for SDF-1alpha-induced migration of epitheloid carcinoma cells.
Peng
Sheng-Bin
SB
Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, Indiana 46285, USA. Peng_Sheng-Bin@Lilly.com
Peek
Victoria
V
Zhai
Yan
Y
Paul
Donald C
DC
Lou
Qinyuan
Q
Xia
Xiaoling
X
Eessalu
Thomas
T
Kohn
Wayne
W
Tang
Shaoqing
S
D002465:Cell Movement / Q000502:physiology*; D054377:Chemokine CXCL12; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006367:HeLa Cells; D006801:Humans; D007457:Iodine Radioisotopes; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism*; D011518:Proto-Oncogene Proteins / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4 / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction / Q000502:physiology
D054377:Chemokine CXCL12; D019743:Chemokines, CXC; D007457:Iodine Radioisotopes; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D019869:Phosphatidylinositol 3-Kinases; D017346:Protein Serine-Threonine Kinases; D011518:Proto-Oncogene Proteins; D051057:Proto-Oncogene Proteins c-akt; D019718:Receptors, CXCR4; C515255:CXCL12 protein, human; C494918:AKT1 protein, human