Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells.

Autor: Pérez-Moreno P; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Indo S; Departamento de Tecnología Médica, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Niechi I; Instituto de Bioquímica y Microbiología, Facultad de Ciencias, Universidad Austral de Chile, Valdivia, Chile., Huerta H; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Cabello P; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Jara L; Programa de Genética Humana, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Aguayo F; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile., Varas-Godoy M; Centro de Investigación Biomédica, Facultad de Medicina, Universidad de Los Andes, Santiago, Chile., Burzio VA; Facultad de Ciencias de la Vida, Universidad Andrés Bello, Santiago, Chile.; Fundación Ciencia & Vida, Andes Biotechnologies SpA, Santiago, Chile., Tapia JC; Departamento de Oncología Básico Clínica, Facultad de Medicina, Universidad de Chile, Santiago, Chile.
Jazyk: angličtina
Zdroj: Molecular oncology [Mol Oncol] 2020 Feb; Vol. 14 (2), pp. 347-362. Date of Electronic Publication: 2019 Dec 19.
DOI: 10.1002/1878-0261.12609
Abstrakt: 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 (ECE1c K6R ) significantly impairs proteasomal degradation, thereby augmenting ECE1c stability, even in the presence of the CK2 inhibitor silmitasertib. Furthermore, colorectal cancer cells overexpressing ECE1c K6R 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.
(© 2019 The Authors. Published by FEBS Press and John Wiley & Sons Ltd.)
Databáze: MEDLINE
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