Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells
Protein Tyrosine Phosphatase-1B Inhibition Disrupts IL13Rα2-Promoted Invasion and Metastasis in Cancer Cells
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DOI：
10.3390/cancers12020500
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发表时间：
2020-02-01
期刊：
影响因子：
5.2
通讯作者：
Ignacio Casal, J.
中科院分区：
文献类型：
--
作者：
Bartolome, Ruben A.;Martin-Regalado, Angela;Ignacio Casal, J.
背景：白细胞介素13受体α 2亚基（IL13R α 2）在胶质母细胞瘤（GBM）、转移性结直肠癌（CRC）和卵巢癌（OC）中过表达。在这里，我们研究了IL13R α 2相互作用组，寻找癌症侵袭和转移的新靶点。方法：采用蛋白质组学分析方法测定了IL13R α 2在GBM中的相互作用，并在CRC和OC中进行了验证。采用siRNA干扰、蛋白酪氨酸磷酸酶- 1b （PTP1B）抑制剂和Western blot分析细胞信号传导。采用GBM和转移性结直肠癌动物模型检测PTP1B抑制剂。结果：PTP1B被鉴定并证实是IL13R α 2信号的中介。一项计算机分析显示，PTP1B过表达与三种类型癌症患者的总生存率较低有关。PTP1B沉默或用PTP1B抑制剂Claramine治疗，通过抑制Src Tyr（530）的去磷酸化，从而抑制Src Tyr（419）、AKT和ERK1/2的磷酸化，显著降低il -13介导的表达IL13R α 2的癌细胞的粘附、迁移和侵袭。此外，Claramine抑制egf介导的EGFR Tyr的激活（1068）。在体内用克拉里明处理可完全抑制CRC细胞接种小鼠的肝转移，并显著增加颅内GBM患者来源的异种移植物小鼠的存活率。结论：我们已经发现，通过IL13R α 2传递的IL13信号需要PTP1B活性，因此，PTP1B抑制在多种类型的癌症（包括胶质母细胞瘤）中代表了一种有希望的治疗策略。
Background: Interleukin 13 receptor alpha 2 subunit (IL13R alpha 2) is overexpressed in glioblastoma (GBM), metastatic colorectal cancer (CRC) and ovarian cancer (OC). Here, we investigated the IL13R alpha 2 interactome searching for novel targets in cancer invasion and metastasis. Methods: The interactome of IL13R alpha 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 alpha 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 alpha 2-expressing cancer cells by inhibiting the dephosphorylation of Src Tyr(530) and consequently, the phosphorylation of Src Tyr(419), AKT and ERK1/2. In addition, Claramine inhibited EGF-mediated activation of EGFR Tyr(1068.) 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 alpha 2 requires PTP1B activity and therefore, PTP1B inhibition represents a promising therapeutic strategy in multiple types of cancer, including glioblastoma.