Abstract
Background: Interleukin 13 receptor alpha 2 subunit (IL13Rα2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). Here, we investigated the IL13Rα2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13Rα2 was determined in GBM by using a proteomic analysis and then validated in CRC and OC. Cell signaling was investigated using siRNA interference, protein tyrosine phosphatase-1B (PTP1B) inhibitors and Western blot analysis. Animal models of GBM and metastatic CRC were used for testing PTP1B inhibitors. Results: PTP1B was identified and validated as a mediator of IL13Rα2 signaling. An in silico analysis revealed that PTP1B overexpression is associated with lower overall survival of patients in the three types of cancer. PTP1B silencing or treatment with Claramine, a PTP1B inhibitor, caused a significant decrease in IL-13-mediated adhesion, migration and invasion of IL13Rα2-expressing cancer cells by inhibiting the dephosphorylation of Src Tyr530 and consequently, the phosphorylation of Src Tyr419, AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr1068. In vivo treatment with Claramine caused a total inhibition of liver metastasis in mice inoculated with CRC cells and a significant increase in the survival of mice bearing intracranial GBM patient-derived xenografts. Conclusions: We have uncovered that IL13 signaling through IL13Rα2 requires PTP1B activity and therefore, PTP1B inhibition represents a promising therapeutic strategy in multiple types of cancer, including glioblastoma.
Highlights
IL13Rα2 has been classified as a cancer/testis-like tumor antigen encoded in chromosome X [1].In normal tissues, IL13Rα2 is mainly expressed in the testis
Our main findings were that (i) protein tyrosine phosphatase-1B (PTP1B) was present in the IL13Rα2 interactome network, (ii) PTP1B was shown to interact with the cytoplasmic tail of IL13Rα2 through phospho-Tyr369, (iii) IL-13 triggered PTP1B-mediated activation of Src followed by activation of PI3K/AKT and ERK pathways, (iv) Claramine, a PTP1B inhibitor, abolished the IL-13 pro-invasive and pro-metastatic effects and (v)
We uncovered the relevance of PTP1B-mediated Src activation for IL-13 signaling through IL13Rα2 in multiple types of cancer
Summary
IL13Rα2 has been classified as a cancer/testis-like tumor antigen encoded in chromosome X [1].In normal tissues, IL13Rα2 is mainly expressed in the testis. IL13Rα2 is overexpressed in a variety of tumor types such as colorectal cancer (CRC), renal cell carcinoma, pancreatic, melanoma, head and neck, mesothelioma, ovarian cancer (OC) and glioblastoma (GBM), among others [2,3,4,5,6,7,8,9]. Interleukin 13 receptor alpha 2 subunit (IL13Rα2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). We investigated the IL13Rα2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13Rα2 was determined in GBM by using a proteomic analysis and validated in CRC and OC. An in silico analysis revealed that PTP1B overexpression is associated with lower overall survival of patients in the three types of cancer.
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