The chemokine CXCL1 induces proliferation in epithelial ovarian cancer cells by transactivation of the epidermal growth factor receptor

Abstract

The chemokine CXCL1 is elevated in plasma and ascites from patients with ovarian cancer. We have previously shown that CXCL1 is a marker of phosphatidylinositol 3-kinase signalling in epithelial ovarian cancer (EOC) cell lines, a pathway that is commonly activated in ovarian tumours. To investigate whether CXCL1 also has functional significance in ovarian cancer, this chemokine was either down-regulated using siRNAs or overexpressed by transfection of CXCL1 into the EOC cell lines SKOV3 and OVCAR-3 and proliferation assessed over 7 days. Overexpression of CXCL1 increased proliferation of ovarian cancer cells over 7 days, while down-regulation was inhibitory. Treatment of cells with recombinant CXCL1 induced epidermal growth factor receptor (EGFR) phosphorylation at Y1068, indicating crosstalk between the CXCL1 G-protein-coupled receptor CXCR2 and the EGFR. CXCL1-induced proliferation was also decreased by inhibition of EGFR kinase activity and was dependent on extracellular matrix metalloproteinase-mediated release of heparin-binding EGF (HB-EGF). Involvement of mitogenactivated protein kinase (MAPK)/extracellular signal-regulated kinase 1/2 (ERK1/2) signalling was also evident since inhibition of both Ras and MEK activity decreased CXCL1-induced proliferation. CXCL1-induced ERK1/2 phosphorylation was inhibited by the MEK1 inhibitor PD98059; however, EGFR phosphorylation was unaffected, indicating that CXCL1 activation of MAPK signalling is downstream of the EGFR. Taken together, these data show that CXCL1 functions through CXCR2 to transactivate the EGFR by proteolytic cleavage of HB-EGF, leading to activation of MAPK signalling and increased proliferation of EOC cells.

G31P, an Antagonist against CXC Chemokine Receptors 1 and 2, Inhibits Growth of Human Prostate Cancer Cells in Nude Mice

“…Thus, multiple small molecule inhibitors of the most important chemokine receptors, CXCR1 and CXCR2, have been generated. A few of these inhibitors showed efficacy in the treatment of experimental cancers (Bolitho et al 2010;Tazzyman et al 2011;Varney et al 2011). In this study, we determined the effects of our newly synthesized CXCR1/2 inhibitor G31P in prostate cancer cells.…”

The Multifaceted Roles Neutrophils Play in the Tumor Microenvironment

“…On the other hand, CCL2 prevents apoptosis of neutrophils [245] and activates neutrophils in the pre-metastatic lung towards an anti-tumor phenotype where they produce H 2 O 2 to kill disseminated tumor cells [32,66], suggesting a dual role of this chemokine. Also, CXCL1 was shown to promote tumor cell proliferation [246], tumor angiogenesis [247], invasion and migration [248], in addition to its ability to recruit and activate neutrophils [249]. CXCL1 was shown to be involved in a paracrine network mediating both metastatic progression and chemoresistance [250].…”

The emerging role of CXC chemokines in epithelial ovarian cancer

“…Both CXCL8 (Schutyser et al 2002) and CXCL1 (Bolitho et al 2010) are up-regulated in ascites fluid, while CXCL8 protein and anti-CXCL8 antibodies are also present in serum from advanced EOC patients (Lokshin et al 2006). Stimulation by CXCL8 of various ovarian tumour cell lines leads to their proliferation in vitro (Wang et al 2005) and is correlated with increased metastatic potential in SKOV3 cells (Yin et al 2011).…”

“…Over-expression of CXCL1 in vitro also results in increased cell proliferation (Bolitho et al 2010). CXCL1 has been shown to promote malignant transformation of epithelial cells through a complex RAS pathway-mediated transformation, which induces normal stroma to 're-program' and become tumorigenic (Yang et al 2006).…”