Abstract 527: Proinflammatory chemokine receptor CXCR2 promotes cellular proliferation through suppression of cell cycle inhibitor p21 protein in ovarian cancer.

Introduction: Ovarian cancer is responsible for the highest rate of mortality in gynecological malignancy. Increased expression for proinflammatory chemokine receptor CXCR2 and its ligand CXCL1 in ovarian cancer have been shown to be associated with poor patient outcomes. However, the mechanisms regulating the interplay between CXCR2 and ovarian cancer remain poorly understood. This study was designed to assess the role and molecular mechanisms of CXCR2 in ovarian cancer cell progression. Methods: The influence of CXCR2 on cell proliferation was examined in CXCR2 null ovarian cancer cells A2780, OVCAR3 and SKOV3, and its stable transfected cells as a molecular tool. The signaling pathways and related genes and protein expressions were determined by Western blot, PCR array and promoter activity assay. Results: CXCR2 promoted cell proliferation in all ovarian cancer cell lines examined. CXCL1, a CXCR2 ligand, further enhanced the potentiation of CXCR2 in cell proliferation. PCR array for cell cycle-related genes displayed inhibited expression for cell cycle inhibitor p21 gene in CXCR2 expressing cells. Western blotting showed that CXCR2 decreased tumor suppressor p53 protein, a tightly regulator for p21, particularly in p53 wild-type A2780 cells. Interestingly, CXCR2 down-regulated histone deacetylase inhibitor (romidepsin)-induced p21 protein expression, even in p53 mutant OVCAR-3 and p53 null SKOV-3 cells, implying the interaction between CXCR2 and p21 protein in a p53-indepentent manner. Nutlin-3, a p53 stabilizer, inhibited ovarian cancer cell proliferation in p53 wild-type cells, and CXCR2 expressing cells were more responsive to nutlin-3 in cell proliferation, indicating the substantial impact of nutlin-3 on p53 stabilization. On the other hand, nutlin-3 had no or little effect on cell proliferation in p53 mutant or null cells. Furthermore, a CXCR2 antagonist, SB225002, recovered the CXCR2-induced down-regulation of p21 protein, and the expression for murine double minute (Mdm2), an important negative regulator of p53, was enhanced in CXCR2 expressing cells. As an evidence to regulate Mdm2, CXCR2 activated epidermal growth factor receptor (EGFR) followed by PI3k/Akt phosphorylation, suggesting the involvement of Akt signaling in the induction of Mdm2 protein. Conclusions: CXCL2-induced cell proliferation is specifically mediated by suppressing cell cycle inhibitor p21 protein, probably resulting from EGFR-Akt-Mdm2 signaling. Therefore, targeting this signaling pathway may represent a potential therapeutic and prophylactic approach for CXCR2 expressing cancer cells. Citation Format: Yuanlin Dong, Syeda M. Kabir, Eunsook Lee, Deok-Soo Son. Proinflammatory chemokine receptor CXCR2 promotes cellular proliferation through suppression of cell cycle inhibitor p21 protein in ovarian cancer. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 527. doi:10.1158/1538-7445.AM2013-527