Browsing by Author "Roa, Juan"

Now showing 1 - 4 of 4
  • Thumbnail Image
    Publication
    A Novel Gemcitabine-Resistant Gallbladder Cancer Model Provides Insights into Molecular Changes Occurring during Acquired Resistance
    (2023) Vergara, Luis; Bizama, Carolina; Zhong, Jun; Buchegger, Kurt; Suárez, Felipe; Rosa, Lorena; Ili, Carmen; Weber, Helga; Obreque, Javiera; Espinoza, Karena; Repetto, Gabriela; Roa, Juan; Leal, Pamela; García, Patricia
    Treatment options for advanced gallbladder cancer (GBC) are scarce and usually rely on cytotoxic chemotherapy, but the effectiveness of any regimen is limited and recurrence rates are high. Here, we investigated the molecular mechanisms of acquired resistance in GBC through the development and characterization of two gemcitabine-resistant GBC cell sublines (NOZ GemR and TGBC1 GemR). Morphological changes, cross-resistance, and migratory/invasive capabilities were evaluated. Then, microarray-based transcriptome profiling and quantitative SILAC-based phosphotyrosine proteomic analyses were performed to identify biological processes and signaling pathways dysregulated in gemcitabine-resistant GBC cells. The transcriptome profiling of parental and gemcitabine-resistant cells revealed the dysregulation of protein-coding genes that promote the enrichment of biological processes such as epithelial-to-mesenchymal transition and drug metabolism. On the other hand, the phosphoproteomics analysis of NOZ GemR identified aberrantly dysregulated signaling pathways in resistant cells as well as active kinases, such as ABL1, PDGFRA, and LYN, which could be novel therapeutic targets in GBC. Accordingly, NOZ GemR showed increased sensitivity toward the multikinase inhibitor dasatinib compared to parental cells. Our study describes transcriptome changes and altered signaling pathways occurring in gemcitabine-resistant GBC cells, which greatly expands our understanding of the underlying mechanisms of acquired drug resistance in GBC.
  • Thumbnail Image
    Publication
    Data Resource Profile: EULAT Eradicate GBC: the European-Latin American Research Consortium towards Eradication of Preventable Gallbladder Cancer
    (2025) Scherer, Dominique; Barahona, Carol; Mengoa, Claudio; Montenegro, Paola; Losada, Hector; Lineth, Ana; Rojas, Armando; Vera, Allan; Spencer, Loreto; Ortega, Alejandro; Vargas, Karina; Roa, Juan; Inklemona, Cristina; Colombo, Alicia; Kirsten, Romy; Zollner, Linda; Marcelain, Katherine; Rounge, Trine; Langseth, Hilde; Lewis, Sarah; Arroyo, Gerardo; Armisen, Ricardo; Nervi, Bruno; Muller, Bettina; Fernandez, Piga; Kumar, Rajiv; Salinas, Pamela; Kelly, Rachel; Jenab, Mazda; Bermejo, Justo
  • Thumbnail Image
    Publication
    LINC00662 Promotes Aggressive Traits by Modulating OCT4 Expression through miR-335-5p in Gallbladder Cancer Cells
    (2024) Perez Moreno, Pablo; Riquelme, Ismael; Bizama, Carolina; Vergara, Luis; Tapia, Julio; Brebi, Priscilla; García, Patricia; Roa, Juan
  • Thumbnail Image
    Publication
    PKR-driven ISR signaling controls synaptic translation and structural plasticity in an age-dependent manner
    (2025) Martínez, Nicolás; Gómez, Felipe; Tapia, Ariel; Roa, Juan; Moreso, Fernanda; Liu, Yuwei; Jara, Claudia; Tapia, Cheril; Alfaro, Ivan; Costa, Mauro; Matus, Soledad
    The integrated stress response (ISR) modulates protein homeostasis in response to both intracellular and extracellular signals. The four kinases involved in the ISR all phosphorylate the same target, the alpha subunit of eukaryotic initiation factor 2 (eIF2α), to integrate various stress signals, thereby regulating cell fate. The activation of the ISR reprograms the proteome by inhibiting general protein synthesis while increasing the translation of specific mRNAs. In the brain, the ISR regulates the type of synaptic plasticity necessary for forming long-term memory. More importantly, the activation of the ISR has emerged as a causal mechanism underlying cognitive decline associated with a wide range of neurological disorders, prompting several pharmaceutical companies to target the ISR to promote brain health. However, whether the ISR acts at specific localities within neurons, including synapses, remains unclear. Here, we examined the presence, activity, and spatial arrangement of the ISR branch driven by the double-stranded RNA-dependent protein kinase (PKR) (PKR-eIF2α axis) in synapses and assessed the role of PKR in maintaining synaptic proteostasis over time. Our findings demonstrate that both PKR and eIF2α are localized at synapses, where a dynamic PKR-eIF2α axis regulates synaptic size and the abundance of synaptic proteins in an age-dependent manner. Moreover, PKR deficiency leads to an increase in protein synthesis in synapse-enriched fractions. Thus, the PKR branch of the ISR serves as a new regulator of synaptic structural plasticity.

Implementado por OpenGeek Services