Akt Activation, but not Extracellular Signal–Regulated Kinase Activation, Is Required for SDF-1A/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 I-SDF-1A ligand binding analyses. The treatment of HeLa cells with recombinant SDF-1A results in time-dependent Akt and extracellular signal–regulated kinase 1/2 (ERK1/2) activations. The SDF-1A–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-1A–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-1A 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-1A–induced migration, suggesting that Akt activation, but not ERK1/2 activation, is required for SDF-1A–induced migration of epitheloid carcinoma cells. (Mol Cancer Res 2005;3(4):227–36)