RESUMEN
The acidic, hypoxic and nutrient-deprived tumor microenvironment may induce endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) may exert an important cytoprotective role by promoting folding of newly synthesized proteins and cancer cell survival. The lack of DNMT2/TRDMT1 methyltransferase-mediated C38 tRNA methylation compromises translational fidelity that may result in the accumulation of misfolded and aggregated proteins leading to proteotoxic stress-related cell death. In the present study, DNMT2/TRDMT1 gene knockout-mediated effects were investigated during doxorubicin (DOX)-induced ER stress and PERK-, IRE1- and ATF6-orchestrated UPR in four genetically different cellular models of cancer (breast and cervical cancer, osteosarcoma and glioblastoma cells). Upon DOX stimulation, DNMT2/TRDMT1 gene knockout impaired PERK activation and modulated NSUN and 5-methylcytosine RNA-based responses and microRNA profiles. The lack of DNMT2/TRDMT1 gene in DOX-treated four cancer cell lines resulted in decreased levels of four microRNAs, namely, miR-23a-3p, miR-93-5p, miR-125a-5p and miR-191-5p involved in the regulation of several pathways such as ubiquitin-mediated proteolysis, amino acid degradation and translational misregulation in cancer. We conclude that DNMT2/TRDMT1 gene knockout, at least in selected cellular cancer models, affects adaptive responses associated with protein homeostasis networks that during prolonged ER stress may result in increased sensitivity to apoptotic cell death.
Asunto(s)
MicroARNs , Neoplasias , Apoptosis/genética , Doxorrubicina/farmacología , eIF-2 Quinasa/genética , Estrés del Retículo Endoplásmico/genética , Técnicas de Inactivación de Genes , Metiltransferasas/genética , Metiltransferasas/metabolismo , Metiltransferasas/farmacología , MicroARNs/genética , Respuesta de Proteína Desplegada/genética , HumanosRESUMEN
Phase composition, crystal structure, and selected physicochemical properties of the high entropy Ln(Co,Cr,Fe,Mn,Ni)O3-δ (Ln = La, Pr, Gd, Nd, Sm) perovskites, as well as the possibility of Sr doping in Ln1-xSrx(Co,Cr,Fe,Mn,Ni)O3-δ series, are reported is this work. With the use of the Pechini method, all undoped compositions are successfully synthesized. The samples exhibit distorted, orthorhombic or rhombohedral crystal structure, and a linear correlation is observed between the ionic radius of Ln and the value of the quasi-cubic perovskite lattice constant. The oxides show moderate thermal expansion, with a lack of visible contribution from the chemical expansion effect. Temperature-dependent values of the total electrical conductivity are reported, and the observed behavior appears distinctive from that of non-high entropy transition metal-based perovskites, beyond the expectations based on the rule-of-mixtures. In terms of formation of solid solutions in Sr-doped Ln1-xSrx(Co,Cr,Fe,Mn,Ni)O3-δ materials, the results indicate a strong influence of the Ln radius, and while for La-based series the Sr solubility limit is at the level of xmax = 0.3, for the smaller Pr it is equal to just 0.1. In the case of Nd-, Sm- and Gd-based materials, even for the xSr = 0.1, the formation of secondary phases is observed on the SEM + EDS images.