CXCR2-Driven Ovarian Cancer Progression Involves Upregulation of Proinflammatory Chemokines by Potentiating NF-kB Activation via EGFR-Transactivated Akt Signaling

Ovarian cancer is an inflammation-associated malignancy with a high mortality rate. CXCR2 expressing ovarian cancers are aggressive with poorer outcomes. We therefore investigated molecular mechanisms involved in CXCR2-driven cancer progression by comparing CXCR2 positive and negative ovarian cancer cell lines. Stably CXCR2 transfected SKOV-3 cells had a faster growth rate as compared to control cells transfected with empty vector. Particularly, tumor necrosis factor (TNF), abundantly expressed in ovarian cancer, enhanced cell proliferation by decreasing the G0-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-kB (NF-kB) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of IkB. CXCR2 transfected cells expressed higher levels of its proinflammatory ligands, CXCL1/2 and enhanced more proliferation, migration, invasion and colony formation. CXCR2 positive cells also activated more EGFR, which led to higher Akt activation. Enhanced NF-kB activity in CXCR2 positive cells was reduced by a PI3K/Akt inhibitor rather than an Erk inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of IkB. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-kB inhibitor, Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF-kB inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-kB site. Thus augmentation of proinflammatory chemokines CXCL1/2, by potentiating NF-kB activation through EGFR-transactivated Akt