CXCR2-Driven Ovarian Cancer Progression Involves Upregulation of Proinflammatory Chemokines by Potentiating NF-κB 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 GO-G1 phase in CXCR2 transfected cells. TNF increased nuclear factor-kappa B (NF-kappa B) activity to a greater degree in CXCR2 transfected cells than control cells as well as provided a greater activation of I kappa B. CXCR2 transfected cells expressed higher levels of its proinflarnmatory 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-kappa B activity in CXCR2 positive cells was reduced by a PI3K/Akt nhibitor rather than an Ek inhibitor. CXCL1 added to CXCR2 positive cells led to an increased activation of I kappa B. CXCL1 also led to a significantly greater number of invasive cells in CXCR2 transfected cells, which was blocked by the NF-kappa B inhibitor Bay 11-7082. In addition, enhanced cell proliferation in CXCR2 positive cells was more sensitive to CXCL1 antibody or an NF kappa B inhibitor. Finally, CXCR2 transfection of parental cells increased CXCL1 promoter activity via an NF-kappa B site. Thus aumentation of proinflammatonj chemokines CXCL1/2 by potentiating NF-kappa B activation through EGFR-transactivated Akt, contributes to CXCR2-driven ovarian cancer progression.