Abstract 1090: Impact of CXCL1/CXCR2 signaling in ovarian cancer proliferation

Abstract

Abstract Introduction: Chemokine network plays a critical role in the development and progression of cancer. Human ovarian tumors express chemokine CXCL1 and its receptor CXCR2, but its role in ovarian cancer development and progression remains unclear. In this study, we investigate whether CXCL1/CXCR2 have functional significance in ovarian cancer cell proliferation. Methods: CXCR2 was overexpressed by stable transfection into the human ovarian surface epithelial cancer cell lines A2780, OVCAR3, and SKOV3. The influence of CXCL1 and CXCR2 on cell proliferation, cell cycle progression, and changes in related proteins and gene expression were determined by using confocal image analysis, MTT assay, Western blotting, flow cytometry, and PCR array. Results: CXCR2 was mainly expressed on the cell surface and intracellular localization, and these expressions were profoundly enhanced in CXCR2 overexpressed cell lines when compared to controls. CXCR2 significantly increased the proliferation of A2780, OVCAR3 and SKOV3 cells in a time-dependent manner, and these increases were abolished by the CXCR2 inhibitor, SD 225002. Furtermore, CXCR2-induced cancer cell proliferation was suppressed by Gefitinib, an inhibitor of epidermal growth factor receptor (EGFR), indicating crosstalk between CXCR2 and EGFR in ovarian cancer cell proliferation. CXCR2 induced phosphorylation of extracellular signal-regulated kinase 1/2 (ERK1/2) and NF-kappa B, probably contributing to ovarian tumor growth and metastatic progression. CXCL1 significantly stimulates the cell proliferation in CXCR2 overexpressed cell lines, and the stimulations were substantially blocked by the ERK1/2 inhibitor, PD 98059, further confirming the involvement of MAPK signaling. CXCR2 reduced cell cycle arrest in the G0-G1 phase and increased the cell population in the S and G2-M phase, and these changes were associated with enhanced expression for CDK6, a G1-S cell cycle transition regulatory gene. Chemokine specific PCR array revealed that CXCR2 enhances proinflammatory chemokines CCL2, CXCL1, CXCL2, CXCL3, and CXCL6, suggesting that CXCR2 accelerates proinflammatory tumor microenvironment to provide the suitable condition for ovarian cancer progression. Conclusions: Taken together, this study demonstrated that CXCL1/CXCR2 signaling plays critical roles in ovarian cancer growth and progression through the activation of ERK1/2 and NF-kappa B. Thus, CXCL1/CXCR2 signaling may be important in the pathogenesis of ovarian cancer, providing a basis for the therapeutic targets in ovarian cancer patients. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 1090. doi:1538-7445.AM2012-1090