CXCR2 Promotes Ovarian Cancer Growth through Dysregulated Cell Cycle, Diminished Apoptosis, and Enhanced Angiogenesis

Abstract

Purpose: Chemokine receptor CXCR2 is associated with malignancy in several cancer models; however, the mechanisms involved in CXCR2-mediated tumor growth remain elusive. Here, we investigated the role of CXCR2 in human ovarian cancer.Experimental Design: CXCR2 expression was silenced by stable small hairpin RNA in ovarian cancer cell lines T29Gro-1, T29H, and SKOV3. Western blotting, immunofluorescence, enzyme-linked immunosorbent assay, flow cytometry, electrophoretic mobility shift assay, and mouse assay were used to detect CXCR2, interleukin-8, Gro-1, cell cycle, apoptosis, DNA binding of NF-κB, and tumor growth. Immunohistochemical staining of CXCR2 was done in 240 high-grade serous ovarian carcinoma samples.Results: Knockdown of CXCR2 expression by small hairpin RNA reduced tumorigenesis of ovarian cancer cells in nude mice. CXCR2 promoted cell cycle progression by modulating cell cycle regulatory proteins, including p21 (waf1/cip1), cyclin D1, CDK6, CDK4, cyclin A, and cyclin B1. CXCR2 inhibited cellular apoptosis by suppressing phosphorylated p53, Puma, and Bcl-xS; suppressing poly(ADP-ribose) polymerase cleavage; and activating Bcl-xL and Bcl-2. CXCR2 stimulated angiogenesis by increasing levels of vascular endothelial growth factor and decreasing levels of thrombospondin-1, a process likely involving mitogen-activated protein kinase, and NF-κB. Overexpression of CXCR2 in high-grade serous ovarian carcinomas was an independent prognostic factor of poor overall survival (P < 0.001) and of early relapse (P = 0.003) in the univariate analysis.Conclusions: Our data provide strong evidence that CXCR2 regulates the cell cycle, apoptosis, and angiogenesis through multiple signaling pathways, including mitogen-activated protein kinase and NF-κB, in ovarian cancer. CXCR2 thus has potential as a therapeutic target and for use in ovarian cancer diagnosis and prognosis. Clin Cancer Res; 16(15); 3875-86. ©2010 AACR.

The CXCR2 Antagonist, SCH-527123, Shows Antitumor Activity and Sensitizes Cells to Oxaliplatin in Preclinical Colon Cancer Models

“…The role of IL-8 and CXCR2 in tumor development and progression has been well documented in a wide range of cancer types (8,(27)(28)(29)(30)(31). Our previous data and others have shown that the IL-8/CXCR2 pathway plays a key role in mediating colorectal cancer development (11,14,15,32).…”

“…IL-8 expression is upregulated by hypoxia, cytokines, and other environmental stresses, which are mediated by transcription factors, including NF-kB and AP-1 (6,7). The upregulation of CXCR2 has also been correlated with promotion of tumorigenesis and angiogenesis in lung, melanoma, and ovarian cancers (8)(9)(10). Previous studies by our group and others have shown that IL-8 and its receptor CXCR2 are significantly upregulated in the tumor and its microenvironment in colorectal cancer (11)(12)(13).…”

Expression of Interleukin-8 Receptor CXCR2 and Suppressor of Cytokine Signaling-3 in Astrocytic Tumors

“…Upregulation of CXCR2 mediates IL-8-induced invasive and migratory phenotype of melanoma cells (24) and is associated with a more aggressive phenotype in hepatocellular (27), gastric (28) and colorectal (29) carcinoma. The mechanisms by which CXCR2 facilitates transformation and migratory responses evoked during oncogenesis are, at least partially, due to manipulation of a comprehensive signaling network comprising phosphati dylinositol 3-kinase/protein kinase B (AKT), nuclear factor κB, Ras, mitogen-activated protein kinase (MAPK) and JAK/STAT-3 (28,(30)(31)(32)(33).…”

The p53 Upregulated Modulator of Apoptosis (PUMA) Chemosensitizes Intrinsically Resistant Ovarian Cancer Cells to Cisplatin by Lowering the Threshold Set by Bcl-xL and Mcl-1

“…On the other hand, elevated PUMA expression, either alone or in combination with chemotherapy or irradiation, induced profound toxicity to a variety of cancer cells, including lung, head and neck, esophagus and breast cancer cells (24)(25)(26)(27). More recently, several studies have shown that PUMA is involved in chemosensitivity via regulating apoptotic signaling pathways (28)(29)(30). However, the role of PUMA in the therapeutic responses of ovarian cancer cells to platinum-based anticancer drugs remains unclear.…”