Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1
The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the p...
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2022-08-01
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| author | Ying Jiang Vitalyi Senyuk Ke Ma Hui Chen Xiang Qin Shun Li Yiyao Liu Saverio Gentile Richard D. Minshall |
| author_facet | Ying Jiang Vitalyi Senyuk Ke Ma Hui Chen Xiang Qin Shun Li Yiyao Liu Saverio Gentile Richard D. Minshall |
| author_sort | Ying Jiang |
| collection | DOAJ |
| description | The prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the pharmacological activation of potassium channel Kv11.1, which is uniquely expressed in MDA-MB-231 triple negative breast cancer cells (TNBCs) but not in normal MCF-10A cells, induces the dephosphorylation of Cav-1 Tyr-14 by promoting the Ca<sup>2+</sup>-dependent stimulation of protein tyrosine phosphatase 1B (PTP1B). Consequently, the dephosphorylation of Cav-1 resulted in its disassociation from β-catenin, which enabled the accumulation of β-catenin at cell borders, where it facilitated the formation of cell–cell adhesion complexes via interactions with R-cadherin and desmosomal proteins. Kv11.1 activation-dependent Cav-1 dephosphorylation induced with NS1643 also reduced cell migration and invasion, consistent with its ability to regulate focal adhesion dynamics. Thus, this study sheds light on a novel pharmacological mechanism of promoting Cav-1 dephosphorylation, which may prove to be effective at reducing metastasis and promoting contact inhibition. |
| first_indexed | 2024-03-09T10:09:22Z |
| format | Article |
| id | doaj.art-4f5cc0034a684696b1bceb3c29acb8b1 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T10:09:22Z |
| publishDate | 2022-08-01 |
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| spelling | doaj.art-4f5cc0034a684696b1bceb3c29acb8b12023-12-01T22:53:25ZengMDPI AGCells2073-44092022-08-011115246110.3390/cells11152461Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1Ying Jiang0Vitalyi Senyuk1Ke Ma2Hui Chen3Xiang Qin4Shun Li5Yiyao Liu6Saverio Gentile7Richard D. Minshall8Center for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, ChinaDepartment of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USAResearch Resources Center, University of Illinois at Chicago, Chicago, IL 60612, USAResearch Resources Center, University of Illinois at Chicago, Chicago, IL 60612, USACenter for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, ChinaCenter for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, ChinaCenter for Informational Biology, University of Electronic Science and Technology of China, Chengdu 610054, ChinaDepartment of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USADepartment of Pharmacology, University of Illinois at Chicago, Chicago, IL 60612, USAThe prevention of metastasis is a central goal of cancer therapy. Caveolin-1 (Cav-1) is a structural membrane and scaffolding protein shown to be a key regulator of late-stage breast cancer metastasis. However, therapeutic strategies targeting Cav-1 are still lacking. Here, we demonstrate that the pharmacological activation of potassium channel Kv11.1, which is uniquely expressed in MDA-MB-231 triple negative breast cancer cells (TNBCs) but not in normal MCF-10A cells, induces the dephosphorylation of Cav-1 Tyr-14 by promoting the Ca<sup>2+</sup>-dependent stimulation of protein tyrosine phosphatase 1B (PTP1B). Consequently, the dephosphorylation of Cav-1 resulted in its disassociation from β-catenin, which enabled the accumulation of β-catenin at cell borders, where it facilitated the formation of cell–cell adhesion complexes via interactions with R-cadherin and desmosomal proteins. Kv11.1 activation-dependent Cav-1 dephosphorylation induced with NS1643 also reduced cell migration and invasion, consistent with its ability to regulate focal adhesion dynamics. Thus, this study sheds light on a novel pharmacological mechanism of promoting Cav-1 dephosphorylation, which may prove to be effective at reducing metastasis and promoting contact inhibition.https://www.mdpi.com/2073-4409/11/15/2461calpainPTP1Bβ-cateninR-cadherinadherens junctionfocal adhesion complex |
| spellingShingle | Ying Jiang Vitalyi Senyuk Ke Ma Hui Chen Xiang Qin Shun Li Yiyao Liu Saverio Gentile Richard D. Minshall Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 Cells calpain PTP1B β-catenin R-cadherin adherens junction focal adhesion complex |
| title | Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 |
| title_full | Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 |
| title_fullStr | Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 |
| title_full_unstemmed | Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 |
| title_short | Pharmacological Activation of Potassium Channel Kv11.1 with NS1643 Attenuates Triple Negative Breast Cancer Cell Migration by Promoting the Dephosphorylation of Caveolin-1 |
| title_sort | pharmacological activation of potassium channel kv11 1 with ns1643 attenuates triple negative breast cancer cell migration by promoting the dephosphorylation of caveolin 1 |
| topic | calpain PTP1B β-catenin R-cadherin adherens junction focal adhesion complex |
| url | https://www.mdpi.com/2073-4409/11/15/2461 |
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