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Published on: February 10, 2023
An IL13Rα2 peptide exhibits therapeutic activity against metastatic colorectal cancer
Rubén A Bartolomé1, Marta Jaén1, J Ignacio Casal2
1Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039, Madrid, Spain.
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.
Insights
A novel peptide targeting Interleukin 13 receptor α2 (IL13Rα2) effectively inhibits cancer cell migration and proliferation. This peptide significantly increases survival rates in mice, offering a promising therapeutic strategy for metastatic colorectal cancer.
Area of Science:
- Oncology
- Molecular Biology
- Cancer Therapeutics
Background:
- Interleukin 13 receptor α2 (IL13Rα2) is frequently overexpressed in metastatic colorectal cancer.
- Targeting IL-13 binding to IL13Rα2 presents a strategy to reduce cancer metastasis.
Purpose of the Study:
- To develop and evaluate novel peptides that block IL-13 binding to IL13Rα2.
- To assess the therapeutic potential of these peptides in reducing metastatic spread.
Main Methods:
- Synthetic IL13Rα2 D1 peptide and its enantiomer D-D1 were synthesized and tested for IL-13 binding inhibition using ELISA and cellular assays.
- Peptide effects on cell signaling mediators were analyzed by western blot.
- In vivo efficacy was evaluated in nude mice for tumor growth and survival.
Main Results:
- The IL13Rα2 D1 peptide inhibited migration, invasion, and proliferation of cancer cells, with specific residues identified as crucial for blocking IL-13.
- The peptide abolished IL-13-mediated receptor internalization and signaling pathways (FAK, PI3K/AKT, Src, MT1-MMP, STAT6).
- Treatment with the D-D1 peptide significantly increased survival in mice.
Conclusions:
- The D-D1 peptide demonstrates potential as a therapeutic agent against metastatic progression in colorectal cancer.
- This approach may be applicable to other solid tumors overexpressing IL13Rα2.
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