Browsing by Author "Carrillo-Beltran, Diego"

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    Cancer Stem Cell and Aggressiveness Traits Are Promoted by Stable Endothelin-Converting Enzyme-1c in Glioblastoma Cells
    (2023) Niechi, Ignacio; Erices, Jose I.; Carrillo-Beltran, Diego; Uribe-Ojeda, Atenea; Torres, Angelo; Rocha, Jose Dellis; Uribe, Daniel; Toro, Maria A.; Villalobos-Nova, Karla; Gaete-Ramirez, Belen; Mingo, Gabriel; Owen, Gareth I. I.; Varas-Godoy, Manuel; Jara, Lilian; Aguayo, Francisco; Burzio, Veronica A.; Quezada-Monras, Claudia; Tapia, Julio C. C.
    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.
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    High-Risk Human Papillomavirus and Epstein-Barr Virus Coinfection: A Potential Role in Head and Neck Carcinogenesis
    (2021) Blanco, Rances; Carrillo-Beltran, Diego; Corvalan, Alejandro H.; Aguayo, Francisco
    Simple Summary A subset of carcinomas that arise in the head and neck region show a viral etiology. In fact, a subgroup of oropharyngeal cancers are caused by some types of human papillomavirus (HPV), so-called high-risk (HR)-HPVs, whereas undifferentiated nasopharyngeal carcinomas are etiologically related to Epstein-Barr virus (EBV). However, studies have reported the presence of both HR-HPV and EBV in some types of head and neck cancers. In this review, we discuss the potential contribution and role of HR-HPV/EBV coinfection in head and neck carcinogenesis, as well as the mechanisms that are potentially involved. In addition, HR-HPV/EBV interaction models are proposed. High-risk human papillomaviruses (HR-HPVs) and Epstein-Barr virus (EBV) are recognized oncogenic viruses involved in the development of a subset of head and neck cancers (HNCs). HR-HPVs are etiologically associated with a subset of oropharyngeal carcinomas (OPCs), whereas EBV is a recognized etiological agent of undifferentiated nasopharyngeal carcinomas (NPCs). In this review, we address epidemiological and mechanistic evidence regarding a potential cooperation between HR-HPV and EBV for HNC development. Considering that: (1) both HR-HPV and EBV infections require cofactors for carcinogenesis; and (2) both oropharyngeal and oral epithelium can be directly exposed to carcinogens, such as alcohol or tobacco smoke, we hypothesize possible interaction mechanisms. The epidemiological and experimental evidence suggests that HR-HPV/EBV cooperation for developing a subset of HNCs is plausible and warrants further investigation.