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

Pablo Pérez-Moreno, Sebastián Indo, Ignacio Niechi, Hernán Huerta, Pablo Cabello, Lilian Jara, Francisco Aguayo, Manuel Varas-Godoy, Verónica A. Burzio, Julio C. Tapia

Resultado de la investigación: Contribución a una revistaArtículo

1 Cita (Scopus)

Resumen

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.

Idioma originalInglés
Páginas (desde-hasta)347-362
Número de páginas16
PublicaciónMolecular Oncology
Volumen14
N.º2
DOI
EstadoEn prensa - 1 ene 2019

Áreas temáticas de ASJC Scopus

  • Medicina molecular
  • Genética
  • Oncología
  • Investigación sobre el cáncer

Huella Profundice en los temas de investigación de 'Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells'. En conjunto forman una huella única.

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    Pérez-Moreno, P., Indo, S., Niechi, I., Huerta, H., Cabello, P., Jara, L., Aguayo, F., Varas-Godoy, M., Burzio, V. A., & Tapia, J. C. (Aceptado/En prensa). Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells. Molecular Oncology, 14(2), 347-362. https://doi.org/10.1002/1878-0261.12609