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Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13R?2-Promoted Invasion and Metastasis in Cancer Cells.


ABSTRACT: Background: Interleukin 13 receptor alpha 2 subunit (IL13R?2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). Here, we investigated the IL13R?2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13R?2 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 IL13R?2 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 IL13R?2-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 IL13R?2 requires PTP1B activity and therefore, PTP1B inhibition represents a promising therapeutic strategy in multiple types of cancer, including glioblastoma.

SUBMITTER: Bartolome RA 

PROVIDER: S-EPMC7072372 | BioStudies | 2020-01-01

REPOSITORIES: biostudies

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