Phosphorylation of Endothelin-Converting Enzyme-1c at Serines 18 and 20 by CK2 Promotes Aggressiveness Traits in Colorectal Cancer Cells.

Autor: Pérez-Moreno P; Programa de Biología Celular y Molecular, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Quezada-Meza C; Programa de Biología Celular y Molecular, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Chavez-Almarza C; Programa de Biología Celular y Molecular, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Niechi I; Facultad de Ciencias, Instituto de Bioquímica y Microbiología, Universidad Austral de Chile, Valdivia, Chile., Silva-Pavez E; Center for Integrative Biology, Faculty of Sciences, Universidad Mayor, Santiago, Chile., Trigo-Hidalgo C; Programa de Biología Celular y Molecular, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Aguayo F; Programa de Virología, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Jara L; Programa de Genética, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile., Cáceres-Verschae A; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Varas-Godoy M; Centro de Biología Celular y Biomedicina, Facultad de Medicina y Ciencia, Universidad San Sebastián, Santiago, Chile., Díaz VM; Unidad Asociada CSIC, Programa de Recerca en Cáncer, Departament de Ciéncies Experimentals i de la Salut, Institut Hospital del Mar d'Investigacions Médiques, Universitat Pompeu Fabra, Barcelona, Spain., García de Herreros A; Unidad Asociada CSIC, Programa de Recerca en Cáncer, Departament de Ciéncies Experimentals i de la Salut, Institut Hospital del Mar d'Investigacions Médiques, Universitat Pompeu Fabra, Barcelona, Spain., Burzio VA; Facultad de Ciencias de la Vida, Universidad Andrés Bello, Fundación Ciencia & Vida, Andes Biotechnologies SpA, Santiago, Chile., Tapia JC; Programa de Biología Celular y Molecular, Facultad de Medicina, ICBM, Universidad de Chile, Santiago, Chile.
Jazyk: angličtina
Zdroj: Frontiers in oncology [Front Oncol] 2020 Jul 30; Vol. 10, pp. 1004. Date of Electronic Publication: 2020 Jul 30 (Print Publication: 2020).
DOI: 10.3389/fonc.2020.01004
Abstrakt: 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 the bona fide residues 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.
(Copyright © 2020 Pérez-Moreno, Quezada-Meza, Chavez-Almarza, Niechi, Silva-Pavez, Trigo-Hidalgo, Aguayo, Jara, Cáceres-Verschae, Varas-Godoy, Díaz, García de Herreros, Burzio and Tapia.)
Databáze: MEDLINE
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