Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells
Endothelin‐1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin‐1 rely on its activation by endothelin‐converting enzyme‐1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1...
| Main Authors: | , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Wiley
2020-02-01
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| Series: | Molecular Oncology |
| Subjects: | |
| Online Access: | https://doi.org/10.1002/1878-0261.12609 |
| _version_ | 1797819796398538752 |
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| author | Pablo Pérez‐Moreno Sebastián Indo Ignacio Niechi Hernán Huerta Pablo Cabello Lilian Jara Francisco Aguayo Manuel Varas‐Godoy Verónica A. Burzio Julio C. Tapia |
| author_facet | Pablo Pérez‐Moreno Sebastián Indo Ignacio Niechi Hernán Huerta Pablo Cabello Lilian Jara Francisco Aguayo Manuel Varas‐Godoy Verónica A. Burzio Julio C. Tapia |
| author_sort | Pablo Pérez‐Moreno |
| collection | DOAJ |
| description | Endothelin‐1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin‐1 rely on its activation by endothelin‐converting enzyme‐1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N‐terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1cK6R) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1cK6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self‐renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2‐dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC‐like traits. Therefore, phospho‐ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer. |
| first_indexed | 2024-03-13T09:27:52Z |
| format | Article |
| id | doaj.art-18a70dfd7d844727ac173a958ee71a6a |
| institution | Directory Open Access Journal |
| issn | 1574-7891 1878-0261 |
| language | English |
| last_indexed | 2024-03-13T09:27:52Z |
| publishDate | 2020-02-01 |
| publisher | Wiley |
| record_format | Article |
| series | Molecular Oncology |
| spelling | doaj.art-18a70dfd7d844727ac173a958ee71a6a2023-05-26T04:31:40ZengWileyMolecular Oncology1574-78911878-02612020-02-0114234736210.1002/1878-0261.12609Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cellsPablo Pérez‐Moreno0Sebastián Indo1Ignacio Niechi2Hernán Huerta3Pablo Cabello4Lilian Jara5Francisco Aguayo6Manuel Varas‐Godoy7Verónica A. Burzio8Julio C. Tapia9Departamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago ChileDepartamento de Tecnología Médica Facultad de Medicina Universidad de Chile Santiago ChileInstituto de Bioquímica y Microbiología Facultad de Ciencias Universidad Austral de Chile Valdivia ChileDepartamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago ChileDepartamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago ChilePrograma de Genética Humana Instituto de Ciencias Biomédicas Facultad de Medicina Universidad de Chile Santiago ChileDepartamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago ChileCentro de Investigación Biomédica Facultad de Medicina Universidad de Los Andes Santiago ChileFacultad de Ciencias de la Vida Universidad Andrés Bello Santiago ChileDepartamento de Oncología Básico Clínica Facultad de Medicina Universidad de Chile Santiago ChileEndothelin‐1 is a mitogenic peptide that activates several proliferation, survival, and invasiveness pathways. The effects of endothelin‐1 rely on its activation by endothelin‐converting enzyme‐1 (ECE1), which is expressed as four isoforms with different cytoplasmic N termini. Recently, isoform ECE1c has been suggested to have a role in cancer aggressiveness. The N terminus of ECE1c is phosphorylated by protein kinase CK2 (also known as casein kinase 2), and this enhances its stability and promotes invasiveness in colorectal cancer cells. However, it is not known how phosphorylation improves stability and why this is correlated with increased aggressiveness. We hypothesized that CK2 phosphorylation protects ECE1c from N‐terminal ubiquitination and, consequently, from proteasomal degradation. Here, we show that lysine 6 is the bona fide residue involved in ubiquitination of ECE1c and its mutation to arginine (ECE1cK6R) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1cK6R displayed enhanced cancer stem cell (CSC) traits, including increased stemness gene expression, chemoresistance, self‐renewal, and colony formation and spheroid formation in vitro, as well as enhanced tumor growth and metastasis in vivo. These findings suggest that CK2‐dependent phosphorylation enhances ECE1c stability, promoting an increase in CSC‐like traits. Therefore, phospho‐ECE1c may be a biomarker of poor prognosis and a potential therapeutic target for colorectal cancer.https://doi.org/10.1002/1878-0261.12609CK2phosphorylationendothelin‐1endothelin‐converting enzymecancer stem cellaggressiveness |
| spellingShingle | Pablo Pérez‐Moreno Sebastián Indo Ignacio Niechi Hernán Huerta Pablo Cabello Lilian Jara Francisco Aguayo Manuel Varas‐Godoy Verónica A. Burzio Julio C. Tapia Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells Molecular Oncology CK2 phosphorylation endothelin‐1 endothelin‐converting enzyme cancer stem cell aggressiveness |
| title | Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| title_full | Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| title_fullStr | Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| title_full_unstemmed | Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| title_short | Endothelin‐converting enzyme‐1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| title_sort | endothelin converting enzyme 1c promotes stem cell traits and aggressiveness in colorectal cancer cells |
| topic | CK2 phosphorylation endothelin‐1 endothelin‐converting enzyme cancer stem cell aggressiveness |
| url | https://doi.org/10.1002/1878-0261.12609 |
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