Chemokine receptors CXCR-1/2 activate mitogen-activated protein kinase viathe epidermal growth factor receptor in ovarian cancer cells

Ovarian cancer typically disseminates widely in the abdomen, a characterist ic that limits curative therapy. The mechanisms that promote ovarian cancer cell migration are incompletely understood. We studied model SK-OV-3 ovari an cancer cells and observed robust expression of the gamma chemokine recep tors CXCR-1 and CXCR-2. Interleukin-8 (IL-8) treatment caused shape changes in the cells, with membrane ruffling and formation/retraction of thin acti n-like projections, as detected by time-lapse microscopy. Stimulation of th e CXCR-1/2 receptors by human interleukin 8 (IL-8) rapidly activated the p4 4/42 mitogen-activated protein (extracellular signal-regulated kinase (Erk1 /2)) kinase pathway. Treatment of SK-OV-3 cells with the inhibitors geneste in and herbimycin A indicated that tyrosine kinases were involved in the IL -8 activation of Erk1 and Erk2. Of note, IL-8 induced transient phosphoryla tion of the epidermal growth factor (EGF) receptor and its association with the adaptor molecules Shc and Grb2. This transactivation of the EGF recept or was dependent on intracellular Ca2+ mobilization. Furthermore AG1478, a specific inhibitor of the EGF receptor kinase, blocked Erk1 and Erk2 activa tion. c-Src kinase was not involved in the LL-g-mediated phosphorylation of the EGF receptor, but was critical for Shc phosphorylation and downstream Erk1/2 kinase activation. These results suggest important "cross-talk" betw een chemokine and growth factor pathways that may link signals of cell migr ation and proliferation in ovarian cancer.