Cancer Stem Cell and Aggressiveness Traits Are Promoted by Stable Endothelin-Converting Enzyme-1c in Glioblastoma Cells

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dc.contributor.authorNiechi, Ignacio
dc.contributor.authorErices, Jose I.
dc.contributor.authorCarrillo-Beltran, Diego
dc.contributor.authorUribe-Ojeda, Atenea
dc.contributor.authorTorres, Angelo
dc.contributor.authorRocha, Jose Dellis
dc.contributor.authorUribe, Daniel
dc.contributor.authorToro, Maria A.
dc.contributor.authorVillalobos-Nova, Karla
dc.contributor.authorGaete-Ramirez, Belen
dc.contributor.authorMingo, Gabriel
dc.contributor.authorOwen, Gareth I. I.
dc.contributor.authorVaras-Godoy, Manuel
dc.contributor.authorJara, Lilian
dc.contributor.authorAguayo, Francisco
dc.contributor.authorBurzio, Veronica A.
dc.contributor.authorQuezada-Monras, Claudia
dc.contributor.authorTapia, Julio C. C.
dc.date.accessioned2025-01-20T20:18:02Z
dc.date.available2025-01-20T20:18:02Z
dc.date.issued2023
dc.description.abstractGlioblastoma (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.
dc.fuente.origenWOS
dc.identifier.doi10.3390/cells12030506
dc.identifier.eissn2073-4409
dc.identifier.urihttps://doi.org/10.3390/cells12030506
dc.identifier.urihttps://repositorio.uc.cl/handle/11534/92437
dc.identifier.wosidWOS:000929317400001
dc.issue.numero3
dc.language.isoen
dc.revistaCells
dc.rightsacceso restringido
dc.subjectglioblastoma
dc.subjectstemness
dc.subjectendothelin
dc.subjectCK2
dc.subjectaggressiveness
dc.subject.ods03 Good Health and Well-being
dc.subject.odspa03 Salud y bienestar
dc.titleCancer Stem Cell and Aggressiveness Traits Are Promoted by Stable Endothelin-Converting Enzyme-1c in Glioblastoma Cells
dc.typeartículo
dc.volumen12
sipa.indexWOS
sipa.trazabilidadWOS;2025-01-12
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