Abstract
Background: Interleukin 13 receptor α2 (IL13Rα2) is overexpressed in metastatic colorectal cancer. Here, we have developed novel strategies to block IL-13 binding to IL13Rα2 in order to reduce metastatic spread. Methods: Synthetic IL13Rα2 D1 peptide (GSETWKTIITKN) was tested for the inhibition of IL-13 binding to IL13Rα2 using ELISA and different cellular assays. Peptide blocking effects on different cell signalling mediators were determined by western blot. An enantiomer version of the peptide (D-D1) was prepared to avoid proteolytic digestion. Nude mice were used for tumour growth and survival analysis after treatment with IL13Rα2 peptides. Results: IL13Rα2 D1 peptide inhibited migration, invasion, and proliferation in metastatic colorectal and glioblastoma cancer cells treated with IL-13. Residues 82K, 83T, 85I and 86T were essential for blocking IL-13. IL13Rα2 peptide abolished ligand-mediated receptor internalisation and degradation, and substantially decreased IL-13 signalling capacity through IL13Rα2 to activate the FAK, PI3K/AKT and Src pathways as well as MT1-MMP expression. In addition, D1 significantly inhibited IL-13-mediated STAT6 activation through IL13Rα1. Nude mice treated with the enantiomer D-D1 peptide showed a remarkable survival increase. Conclusions: We propose that the D-D1 peptide from IL13Rα2 represents a promising therapeutic agent to inhibit metastatic progression in colorectal cancer and, likely, other solid tumours.