Interleukin-8/CXCL8 is a growth factor for human lung cancer cells

Abstract

Interleukin-8/CXCL8 (IL-8) is a chemokine and angiogenic factor. Recently, IL-8 was identified as an autocrine growth factor in several human cancers. Here, we investigated the expression and function of IL-8 in lung cancer cells. The expressions of IL-8 and its receptors, CXCR1 and CXCR2, were examined in a panel of non-small cell lung cancer (NSCLC) and small cell lung cancer (SCLC) cell lines. Using reverse transcription -polymerase chain reaction (RT -PCR) and enzyme-linked immunosorbent assay, we found that all NSCLC cell lines tested produced modest or high levels of IL-8 (up to 51 ng ml À1 10 6 cells À1 ). Expression of CXCR1 and CXCR2 was found by RT -PCR and flow cytometry in two out of three cell lines. In contrast, SCLC cell lines produced very low or undetectable levels of IL-8, but expressed CXCR1 and CXCR2. We next investigated whether IL-8 could act as an autocrine growth factor in two NSCLC cell lines (H460 and MOR/P) expressing both IL-8 and its receptors. We found that cell proliferation was attenuated by anti-IL-8 neutralising antibody to 71 and 76% in H460 and MOR/P, respectively (Po0.05). Exogenous IL-8 significantly stimulated cell proliferation in four SCLC cell lines tested in a dose-dependent fashion. Cell proliferation was increased by between 18% (Po0.05) and 37% (Po0.05). Stimulation of cell proliferation by IL-8 was also demonstrated by analysis of proliferating cell nuclear antigen expression and cell cycle in H69 cells. Furthermore, we investigated which receptor(s) mediated the mitogenic function of IL-8 in lung cancer cells. We found that cell proliferation was significantly reduced by anti-CXCR1 antibody but not by anti-CXCR2 antibody. In conclusion, IL-8 can act as an autocrine and/or paracrine growth factor for lung cancer cells, and the mitogenic function of IL-8 in lung cancer is mediated mainly by CXCR1 receptor.

Production and upregulation of granulocyte chemotactic protein-2/CXCL6 by IL-1β and hypoxia in small cell lung cancer

“…The effects of ELR þ CXC chemokines are mediated through binding to CXCR1 and CXCR2 receptors. All the ELR þ CXC chemokines utilise the CXCR2 receptor, but only IL-8 and GCP-2 recognise the CXCR1 receptor, which we found to be the predominant receptor in lung cancer cells (Zhu et al, 2004). Overexpression of IL-8 has been detected in non-small cell lung cancer (NSCLC), where its expression correlates with tumorigenic and metastatic potential (Yuan et al, 2000;Chen et al, 2003).…”

“…These results suggest that GCP-2 may act as an autocrine growth factor in SCLC cells. , which shares the CXCR1 and CXCR2 receptors with GCP-2, was also found to be mitogenic to SCLC (Zhu et al, 2004). The signal transduction pathways mediating the mitogenic function of IL-8 are complex, include extracellular signal-regulated kinase (ERK) of mitogenactivated protein kinase (MAPK) pathway, NF-kB, and epidermal growth factor receptor (EGFR) pathway by cross-talk (Zhu and Woll, 2005).…”

“…Granulocyte chemotactic protein-2 concentrations in the culture media were determined by ELISA (R&D systems, Abingdon, UK) as previously described for IL-8 (Zhu et al, 2003;Zhu et al, 2004). The concentration of GCP-2 was determined by measuring the optical density (OD) at 450 nm in a Dynatech MR5000 microplate reader.…”

“…We found that whereas NSCLC produced high levels of IL-8, SCLC produced low levels of IL-8. However, SCLC expressed higher levels of the IL-8 receptors, CXCR1 and CXCR2 than NSCLC (Zhu et al, 2004). The only other known ligand for CXCR1 receptor is GCP-2.…”

Characterization of LY2228820 Dimesylate, a Potent and Selective Inhibitor of p38 MAPK with Antitumor Activity

“…Inhibition of p38 MAPK also reduces production of VEGF and plateletderived growth factor by BMSCs in vitro (28). In response to neutrophil elastase, lung cancer cells produce CXCL8, which stimulates the growth of lung cancer cells in vitro (29)(30)(31) in a p38a MAPK-dependent manner, indicating that neutrophils in the TME may activate the p38 MAPK signaling pathway in tumor cells to promote lung cancer growth (32). Furthermore, secretion of CXCL8 by both the tumor and TME increases proliferation of ovarian cancer cells in vitro and in vivo (30,32).…”