Abstract
Cetuximab, which blocks ligand binding to epidermal growth factor receptor (EGFR), is currently being studied as a novel treatment for non-small cell lung cancer (NSCLC). However, its mechanisms of action toward metastasis, and markers of drug sensitivity, have not been fully elucidated. This study was conducted to (a) determine the effect of Cetuximab on invasion and NSCLC-metastasis; (b) investigate urokinase-type plasminogen activator receptor (u-PAR), a major molecule promoting invasion and metastasis, as a target molecule; (c) delineate molecular mediators of Cetuximab-induced metastasis inhibition; and (d) identify biomarkers of drug sensitivity in NSCLC. Cetuximab treatment resulted in reduced growth and Matrigel invasion of H1395 and A549 NSCLC cell lines, in parallel with reduced u-PAR mRNA and protein. u-PAR down-regulation was brought about by suppressing the binding of JunD and c-Jun to u-PAR promoter motif -190/-171 in vivo, and an inhibition of MAP/ERK kinase signaling. Furthermore, Cetuximab inhibited NSCLC proliferation and metastasis to distant organs in vivo as indicated by the chicken embryo metastasis assay. Low E-cadherin and high u-PAR, but not EGFR, was associated with resistance to Cetuximab in seven NSCLC cell lines. Furthermore, siRNA knockdown of u-PAR led to a resensitization to Cetuximab. Moreover, low E-cadherin and high u-PAR was found in 63% of resected tumor tissues of NSCLC patients progressing under Cetuximab therapy. This is the first study to show u-PAR as a target and marker of sensitivity to Cetuximab, and to delineate novel mechanisms leading to metastasis suppression of NSCLC by Cetuximab.
Highlights
Lung cancer is one of the most prevalent cancers [1, 2], non– small cell lung cancer (NSCLC) accounting for 85% of cases [3]
We report the novel finding that Cetuximab reduces the potential of NSCLC to metastasize to distant organs in vivo
We further show the ability of Cetuximab to inhibit epidermal growth factor receptor (EGFR)-downstream signaling via especially MAP kinase (MAPK) and AP-1, leading to the down-regulation of urokinase-type plasminogen activator receptor (u-PAR) gene
Summary
Lung cancer is one of the most prevalent cancers [1, 2], non– small cell lung cancer (NSCLC) accounting for 85% of cases [3]. Epidermal growth factor (EGF) receptor (EGFR) is overexpressed in. Note: Supplementary data for this article are available at Cancer Research Online (http://cancerres.aacrjournals.org/). Http://www.sanger.ac.uk/genetics/CGP/ was used to verify EGFR-wt status in all NSCLC cell lines. NSCLC [4] and correlates with tumor growth, metastasis, and poor prognosis [5]. EGFR is the archetypal member of a superfamily of cell membrane receptors with intrinsic tyrosine kinase activity. The binding of EGFR ligands including EGF, transforming growth factor-a, and heparin-binding EGF initiates receptor dimerization, autophosphorylation of tyrosine residues within the cytoplasmic domain, and recruitment of adaptor proteins, activating signaling molecules downstream [6]. Biological responses to EGFR activation include proliferation, differentiation, motility, and metabolism [7]
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