Extra-virgin olive oil contains a metabolo-epigenetic inhibitor of cancer stem cells
Corominas-Faja B, Cuyàs E, Lozano-Sánchez J, Cufí S, Verdura S, Fernández-Arroyo S, Borrás-Linares I, Martin-Castillo B, Martin ÁG, Lupu R, Nonell-Canals A, Sanchez-Martinez M, Micol V, Joven J, Segura-Carretero A, Menendez JA
Carcinogenesis · 40 citations
How it was studied
- Design
- In vitro/mechanistic study (classified by our AI screen)
- Studied in
- People, plus animal or lab work
- Main outcome
- Clinical events such as disease or death
Who paid for it
- Funding
- Independent funding
- Government
- Ministerio de Ciencia e Innovación
- Government
- Agència de Gestió d'Ajuts Universitaris i de Recerca
- Government
- Ministerio de Sanidad y Consumo, Fondo de Investigación Sanitaria
- Government
- Andalusian Regional Government Council of Innovation and Science
- Government
- Ministerio de Economía, Industria y Competitividad, Spain
- Government
- Conselleria d’Educació, Investigació, Cultura I Esport, Generalitat Valenciana, Spain
- Government
- Agència de Gestió d’Ajuts Universitaris i de Recerca
- Government
- Departament d’Economia i Coneixement, Catalonia, Spain
- Government
- Plan Nacional de I+D+I
- Grants
- Agència de Gestió d'Ajuts Universitaris i de Recerca (SGR229); Ministerio de Ciencia e Innovación (SAF2016‐80639‐P)
Based on 9 listed funder(s) and full-text disclosure statement.
Publication
- Published
- 2018-02-09 · Carcinogenesis · vol. 39 · issue 4 · pp. 601–613
- Publisher
- Oxford University Press
- Cited
- 61 citations · more than 91% of similar papers · 2.6× the field average
- Impact
- Top 10% most cited in its field
- References
- 62 works
- Access
- Open access (hybrid journal) · CC-BY-NC
- Research areas
- MicroRNA in disease regulation · Cancer-related molecular mechanisms research · Epigenetics and DNA Methylation
- Keywords
- Cancer stem cell, Cancer research, In vivo, CD44, Biology, In silico, Stem cell, PI3K/AKT/mTOR pathway, Chemistry, Biochemistry, In vitro, Cell biology, Apoptosis, Genetics
- MeSH
- animals, humans, mice, breast neoplasms, acetates, pyrans, dna modification methylases, plant extracts, xenograft model antitumor assays, female, neoplastic stem cells, tor serine-threonine kinases, olive oil, cyclopentane monoterpenes
16 authors
From ES, US
- Bruna Corominas-FajaInstitut Català d'Oncologia; Institut d'Investigació Biomèdica de Girona
- Elisabet CuyàsInstitut Català d'Oncologia; Institut d'Investigació Biomèdica de Girona
- Jesús Lozano‐SánchezUniversidad de Granada; Parque Tecnológico de la Salud
- Sílvia CufíInstitut d'Investigació Biomèdica de Girona
- Sara VerduraInstitut Català d'Oncologia; Institut d'Investigació Biomèdica de Girona
- Salvador Fernández‐ArroyoInstitut de Recerca Biomèdica Catalunya Sud; Universitat Rovira i Virgili
Abstract
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.
Abstract via Europe PMC. Copyright remains with the authors or publisher (CC BY-NC).
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