An IL13Rα2 peptide exhibits therapeutic activity against metastatic colorectal cancer

BACKGROUND: Interleukin 13 receptor alpha 2 (1L13R alpha 2) is overexpressed in metastatic colorectal cancer. Here, we have developed novel strategies to block IL-13 binding to IL13R alpha 2 in order to reduce metastatic spread. METHODS: Synthetic IL13R alpha 2 D1 peptide (GSETWKTIITKN) was tested for the inhibition of IL-13 binding to IL13R alpha 2 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 1L13R alpha 2 peptides. RESULTS:1L13R alpha 2 D1 peptide inhibited migration, invasion, and proliferation in metastatic colorectal and glioblastoma cancer cells treated with 1L-13. Residues K-82, T-83, I-85 and T-86 were essential for blocking IL-13. IL13R alpha 2 peptide abolished ligand-mediated receptor internalisation and degradation, and substantially decreased IL-13 signalling capacity through IL13R alpha 2 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 IL13R alpha 1. Nude mice treated with the enantiomer D-D1 peptide showed a remarkable survival increase. CONCLUSIONS: We propose that the D-D1 peptide from IL13R alpha 2 represents a promising therapeutic agent to inhibit metastatic progression in colorectal cancer and, likely, other solid tumours.