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: Article

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 originalEnglish
PublicaciónMolecular Oncology
DOI
EstadoAccepted/In press - 1 ene 2019

Huella dactilar

Casein Kinase II
Colorectal Neoplasms
Stem Cells
Neoplastic Stem Cells
Ubiquitination
Phosphorylation
Endothelin-1
Protein Isoforms
Lysine
Arginine
Neoplasms
Biomarkers
Neoplasm Metastasis
Gene Expression
Peptides
Mutation
Growth
Endothelin-Converting Enzymes
Therapeutics

ASJC Scopus subject areas

  • Molecular Medicine
  • Genetics
  • Oncology
  • Cancer Research

Citar esto

Pérez-Moreno, P., Indo, S., Niechi, I., Huerta, H., Cabello, P., Jara, L., ... Tapia, J. C. (Aceptado/En prensa). Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells. Molecular Oncology. https://doi.org/10.1002/1878-0261.12609
Pérez-Moreno, Pablo ; Indo, Sebastián ; Niechi, Ignacio ; Huerta, Hernán ; Cabello, Pablo ; Jara, Lilian ; Aguayo, Francisco ; Varas-Godoy, Manuel ; Burzio, Verónica A. ; Tapia, Julio C. / Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells. En: Molecular Oncology. 2019.
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Pérez-Moreno, P, Indo, S, Niechi, I, Huerta, H, Cabello, P, Jara, L, Aguayo, F, Varas-Godoy, M, Burzio, VA & Tapia, JC 2019, 'Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells', Molecular Oncology. https://doi.org/10.1002/1878-0261.12609

Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells. / Pérez-Moreno, Pablo; Indo, Sebastián; Niechi, Ignacio; Huerta, Hernán; Cabello, Pablo; Jara, Lilian; Aguayo, Francisco; Varas-Godoy, Manuel; Burzio, Verónica A.; Tapia, Julio C.

En: Molecular Oncology, 01.01.2019.

Resultado de la investigación: Article

TY - JOUR

T1 - Endothelin-converting enzyme-1c promotes stem cell traits and aggressiveness in colorectal cancer cells

AU - Pérez-Moreno, Pablo

AU - Indo, Sebastián

AU - Niechi, Ignacio

AU - Huerta, Hernán

AU - Cabello, Pablo

AU - Jara, Lilian

AU - Aguayo, Francisco

AU - Varas-Godoy, Manuel

AU - Burzio, Verónica A.

AU - Tapia, Julio C.

PY - 2019/1/1

Y1 - 2019/1/1

N2 - 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.

AB - 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.

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KW - cancer stem cell

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