Phosphorylation of Endothelin-Converting Enzyme-1c at Serines 18 and 20 by CK2 Promotes Aggressiveness Traits in Colorectal Cancer Cells
Author
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Pérez Moreno, Pablo
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Quezada Meza, Camila
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Chávez Almarza, Cristopher
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Niechi, Ignacio
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Silva Pavez, Eduardo
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Trigo Hidalgo, César
Author
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Aguayo González, Francisco
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Jara Sosa, Lilian
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Cáceres Verschae, Albano
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Varas Godoy, Manuel
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Díaz, Víctor M.
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García de Herreros, Antonio
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Burzio, Verónica A.
Author
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Tapia Pineda, Julio
Admission date
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2020-11-12T00:25:14Z
Available date
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2020-11-12T00:25:14Z
Publication date
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2020
Cita de ítem
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Front. Oncol. July 2020 | Volume 10 | Article 1004
es_ES
Identifier
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10.3389/fonc.2020.01004
Identifier
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https://repositorio.uchile.cl/handle/2250/177680
Abstract
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Endothelin-converting enzyme-1 (ECE1) activates the endothelin-1 peptide, which upregulates pathways that are related to diverse hallmarks of cancer. ECE1 is expressed as four isoforms differing in their N-terminal domains. Protein kinase CK2 phosphorylates the N-terminus of isoform ECE1c, enhancing its stability and promoting invasiveness of colorectal cancer cells. However, the specific residues in ECE1c that are phosphorylated by CK2 and how this phosphorylation promotes invasiveness was unknown. Here we demonstrate that Ser-18 and Ser-20 are thebona fideresidues phosphorylated by CK2 in ECE1c. Thus, biphospho-mimetic ECE1c(DD)and biphospho-resistant ECE1c(AA)mutants were constructed and stably expressed in different colorectal cancer cells through lentiviral transduction. Biphospho-mimetic ECE1c(DD)displayed the highest stability in cells, even in the presence of the specific CK2 inhibitor silmitasertib. Concordantly, ECE1c(DD)-expressing cells showed enhanced hallmarks of cancer, such as proliferation, migration, invasiveness, and self-renewal capacities. Conversely, cells expressing the less-stable biphospho-resistant ECE1c(AA)showed a reduction in these features, but also displayed an important sensitization to 5-fluorouracil, an antineoplastic agent traditionally used as therapy in colorectal cancer patients. Altogether, these findings suggest that phosphorylation of ECE1c at Ser-18 and Ser-20 by CK2 promotes aggressiveness in colorectal cancer cells. Therefore, phospho-ECE1c may constitute a novel biomarker of poor prognosis and CK2 inhibition may be envisioned as a potential therapy for colorectal cancer patients.
es_ES
Patrocinador
dc.description.sponsorship
Ministerio de Economía y Competitividad (MINECO)
European Union (EU)
SAF2016-76461-R
Líneas de Apoyo a la Investigación Financiadas por el ICBM-2019
FONDAP
15130011
Comision Nacional de Investigacion Cientifica y Tecnologica (CONICYT)
CONICYT FONDECYT
3180508
3180621
1161219
1200049
1190928
1140345
1160889