Autor según el artículo: Corominas-Faja B; Cuyàs E; Lozano-Sánchez J; Cufí S; Verdura S; Fernández-Arroyo S; Borrás-Linares I; Martin-Castillo B; Martin Á; Lupu R; Nonell-Canals A; Sanchez-Martinez M; Micol V; Joven J; Segura-Carretero A; Menendez J
Departamento: Medicina i Cirurgia
Autor/es de la URV: Joven Maried, Jorge
Palabras clave: Tumorigenesis Therapy Target Protein Phenotype microarrays Junctional intercellular communication Growth Epithelial-mesenchymal transition Drug discovery Breast-cancer
Resumen: Targeting tumor-initiating, drug-resistant populations of cancer stem cells (CSC) with phytochemicals is a novel paradigm for cancer prevention and treatment. We herein employed a phenotypic drug discovery approach coupled to mechanism-of-action profiling and target deconvolution to identify phenolic components of extra virgin olive oil (EVOO) capable of suppressing the functional traits of CSC in breast cancer (BC). In vitro screening revealed that the secoiridoid decarboxymethyl oleuropein aglycone (DOA) could selectively target subpopulations of epithelial-like, aldehyde dehydrogenase (ALDH)-positive and mesenchymal-like, CD44+CD24-/low CSC. DOA could potently block the formation of multicellular tumorspheres generated from single-founder stem-like cells in a panel of genetically diverse BC models. Pretreatment of BC populations with noncytotoxic doses of DOA dramatically reduced subsequent tumor-forming capacity in vivo. Mice orthotopically injected with CSC-enriched BC-cell populations pretreated with DOA remained tumor-free for several months. Phenotype microarray-based screening pointed to a synergistic interaction of DOA with the mTOR inhibitor rapamycin and the DNA methyltransferase (DNMT) inhibitor 5-azacytidine. In silico computational studies indicated that DOA binds and inhibits the ATP-binding kinase domain site of mTOR and the S-adenosyl-l-methionine (SAM) cofactor-binding pocket of DNMTs. FRET-based Z-LYTE™ and AlphaScreen-based in vitro assays confirmed the ability of DOA to function as an ATP-competitive mTOR inhibitor and to block the SAM-dependent methylation activity of DNMTs. Our systematic in vitro, in vivo and in silico approaches establish the phenol-conjugated oleoside DOA as a dual mTOR/DNMT inhibitor naturally occurring in EVOO that functionally suppresses CSC-like states responsible for maintaining tumor-initiating cell properties within BC populations.
Áreas temáticas: Saúde coletiva Química Oncology Odontología Medicine (miscellaneous) Medicina iii Medicina ii Medicina i Interdisciplinar General medicine Educação física Ciências biológicas iii Ciências biológicas ii Ciências biológicas i Ciência de alimentos Cancer research Biotecnología
Acceso a la licencia de uso: https://creativecommons.org/licenses/by/3.0/es/
ISSN: 01433334
Direcció de correo del autor: jorge.joven@urv.cat
Identificador del autor: 0000-0003-2749-4541
Fecha de alta del registro: 2024-09-07
Versión del articulo depositado: info:eu-repo/semantics/publishedVersion
URL Documento de licencia: https://repositori.urv.cat/ca/proteccio-de-dades/
Referencia al articulo segun fuente origial: Carcinogenesis. 39 (4): 601-613
Referencia de l'ítem segons les normes APA: Corominas-Faja B; Cuyàs E; Lozano-Sánchez J; Cufí S; Verdura S; Fernández-Arroyo S; Borrás-Linares I; Martin-Castillo B; Martin Á; Lupu R; Nonell-Cana (2018). Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells. Carcinogenesis, 39(4), 601-613. DOI: 10.1093/carcin/bgy023
Entidad: Universitat Rovira i Virgili
Año de publicación de la revista: 2018
Tipo de publicación: Journal Publications
Repositori URV