Cancer Stem Cell and Aggressiveness Traits Are Promoted by Stable Endothelin-Converting Enzyme-1c in Glioblastoma Cells.
Ignacio NiechiJosé Ignacio EricesDiego Carrillo-BeltránAtenea Uribe-OjedaÁngelo TorresJosé Dellis RochaDaniel UribeMaría A ToroKarla Villalobos-NovaBelén Gaete-RamírezGabriel MingoGareth I OwenManuel Varas-GodoyLilian JaraFrancisco AguayoVerónica A BurzioClaudia Quezada-MonrásJulio C TapiaPublished in: Cells (2023)
Glioblastoma (GBM) is the most common and aggressive type of brain tumor due to its elevated recurrence following treatments. This is mainly mediated by a subpopulation of cells with stemness traits termed glioblastoma stem-like cells (GSCs), which are extremely resistant to anti-neoplastic drugs. Thus, an advancement in the understanding of the molecular processes underlying GSC occurrence should contribute significantly towards progress in reducing aggressiveness. High levels of endothelin-converting enzyme-1 (ECE1), key for endothelin-1 (ET-1) peptide activation, have been linked to the malignant progression of GBM. There are four known isoforms of ECE1 that activate ET-1, which only differ in their cytoplasmic N-terminal sequences. Isoform ECE1c is phosphorylated at Ser-18 and Ser-20 by protein kinase CK2, which increases its stability and hence promotes aggressiveness traits in colon cancer cells. In order to study whether ECE1c exerts a malignant effect in GBM, we designed an ECE1c mutant by switching a putative ubiquitination lysine proximal to the phospho-serines Lys-6-to-Arg (i.e., K6R). This ECE1c K6R mutant was stably expressed in U87MG, T98G, and U251 GBM cells, and their behavior was compared to either mock or wild-type ECE1c-expressing clone cells. ECE1c K6R behaved as a highly stable protein in all cell lines, and its expression promoted self-renewal and the enrichment of a stem-like population characterized by enhanced neurospheroid formation, as well as increased expression of stem-like surface markers. These ECE1c K6R -derived GSC-like cells also displayed enhanced resistance to the GBM-related chemotherapy drugs temozolomide and gemcitabine and increased expression of the ABCG2 efflux pump. In addition, ECE1c K6R cells displayed enhanced metastasis-associated traits, such as the modulation of adhesion and the enhancement of cell migration and invasion. In conclusion, the acquisition of a GSC-like phenotype, together with heightened chemoresistance and invasiveness traits, allows us to suggest phospho-ECE1c as a novel marker for poor prognosis as well as a potential therapeutic target for GBM.
Keyphrases
- poor prognosis
- induced apoptosis
- cell cycle arrest
- long non coding rna
- wild type
- genome wide
- cell death
- endoplasmic reticulum stress
- cancer stem cells
- risk assessment
- protein kinase
- oxidative stress
- gene expression
- radiation therapy
- signaling pathway
- single cell
- dna methylation
- binding protein
- staphylococcus aureus
- escherichia coli
- newly diagnosed
- biofilm formation
- protein protein