Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells
<i>Background:</i> 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 meta...
| Main Authors: | , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
MDPI AG
2020-02-01
|
| Series: | Cancers |
| Subjects: | |
| Online Access: | https://www.mdpi.com/2072-6694/12/2/500 |
| _version_ | 1797707143559774208 |
|---|---|
| author | Rubén A. Bartolomé Ángela Martín-Regalado Marta Jaén Markella Zannikou Peng Zhang Vivian de los Ríos Irina V. Balyasnikova J. Ignacio Casal |
| author_facet | Rubén A. Bartolomé Ángela Martín-Regalado Marta Jaén Markella Zannikou Peng Zhang Vivian de los Ríos Irina V. Balyasnikova J. Ignacio Casal |
| author_sort | Rubén A. Bartolomé |
| collection | DOAJ |
| description | <i>Background:</i> 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. <i>Methods:</i> 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. <i>Results:</i> 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 Tyr<sub>530</sub> and consequently, the phosphorylation of Src Tyr<sub>419</sub>, AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr<sub>1068.</sub> 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. <i>Conclusions:</i> 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. |
| first_indexed | 2024-03-12T06:03:01Z |
| format | Article |
| id | doaj.art-99b4720efdc245e09a0d8ee7b40c5c98 |
| institution | Directory Open Access Journal |
| issn | 2072-6694 |
| language | English |
| last_indexed | 2024-03-12T06:03:01Z |
| publishDate | 2020-02-01 |
| publisher | MDPI AG |
| record_format | Article |
| series | Cancers |
| spelling | doaj.art-99b4720efdc245e09a0d8ee7b40c5c982023-09-03T03:59:34ZengMDPI AGCancers2072-66942020-02-0112250010.3390/cancers12020500cancers12020500Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer CellsRubén A. Bartolomé0Ángela Martín-Regalado1Marta Jaén2Markella Zannikou3Peng Zhang4Vivian de los Ríos5Irina V. Balyasnikova6J. Ignacio Casal7Department of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, SpainDepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, SpainDepartment of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADepartment of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USAProteomics Core Facility, Centro de Investigaciones Biológicas (CSIC), 28001 Madrid, SpainDepartment of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, IL 60611, USADepartment of Molecular Biomedicine, Centro de Investigaciones Biológicas, CSIC, Ramiro de Maeztu 9, 28039 Madrid, Spain<i>Background:</i> 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. <i>Methods:</i> 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. <i>Results:</i> 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 Tyr<sub>530</sub> and consequently, the phosphorylation of Src Tyr<sub>419</sub>, AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr<sub>1068.</sub> 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. <i>Conclusions:</i> 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.https://www.mdpi.com/2072-6694/12/2/500colorectal canceregfrglioblastomail13rα2metastasisovarian cancerptp1bsrc |
| spellingShingle | Rubén A. Bartolomé Ángela Martín-Regalado Marta Jaén Markella Zannikou Peng Zhang Vivian de los Ríos Irina V. Balyasnikova J. Ignacio Casal Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells Cancers colorectal cancer egfr glioblastoma il13rα2 metastasis ovarian cancer ptp1b src |
| title | Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells |
| title_full | Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells |
| title_fullStr | Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells |
| title_full_unstemmed | Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells |
| title_short | Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells |
| title_sort | protein tyrosine phosphatase 1b inhibition disrupts il13rα2 promoted invasion and metastasis in cancer cells |
| topic | colorectal cancer egfr glioblastoma il13rα2 metastasis ovarian cancer ptp1b src |
| url | https://www.mdpi.com/2072-6694/12/2/500 |
| work_keys_str_mv | AT rubenabartolome proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT angelamartinregalado proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT martajaen proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT markellazannikou proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT pengzhang proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT viviandelosrios proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT irinavbalyasnikova proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells AT jignaciocasal proteintyrosinephosphatase1binhibitiondisruptsil13ra2promotedinvasionandmetastasisincancercells |