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

Research output: Contribution to journalArticlepeer-review

5 Citations (Scopus)

Abstract

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.

Original languageEnglish
Pages (from-to)347-362
Number of pages16
JournalMolecular Oncology
Volume14
Issue number2
DOIs
Publication statusAccepted/In press - 1 Jan 2019

Keywords

  • aggressiveness
  • cancer stem cell
  • CK2
  • endothelin-1
  • endothelin-converting enzyme
  • phosphorylation

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

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