Expression of oncogenic drivers in 3D cell culture depends on nuclear ATP synthesis by NUDT5

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• dc.contributor.author Pickup, Katherine E.
• dc.contributor.author Pardow, Felicitas
• dc.contributor.author Carbonell-Caballero, Jose
• dc.contributor.author Lioutas, Antonio, 1980-
• dc.contributor.author Villanueva Cañas, José Luis, 1984-
• dc.contributor.author Wright, Roni H.G.
• dc.contributor.author Beato, Miguel
• dc.date.accessioned 2020-03-18T07:47:58Z
• dc.date.available 2020-03-18T07:47:58Z
• dc.date.issued 2019
• dc.description.abstract The growth of cancer cells as oncospheres in three-dimensional (3D) culture provides a robust cell model for understanding cancer progression, as well as for early drug discovery and validation. We have previously described a novel pathway in breast cancer cells, whereby ADP (Adenosine diphosphate)-ribose derived from hydrolysis of poly (ADP-Ribose) and pyrophosphate (PPi) are converted to ATP, catalysed by the enzyme NUDT5 (nucleotide diphosphate hydrolase type 5). Overexpression of the NUDT5 gene in breast and other cancer types is associated with poor prognosis, increased risk of recurrence and metastasis. In order to understand the role of NUDT5 in cancer cell growth, we performed phenotypic and global expression analysis in breast cancer cells grown as oncospheres. Comparison of two-dimensional (2D) versus 3D cancer cell cultures from different tissues of origin suggest that NUDT5 increases the aggressiveness of the disease via the modulation of several key driver genes, including ubiquitin specific peptidase 22 (USP22), RAB35B, focadhesin (FOCAD) and prostagladin E synthase (PTGES). NUDT5 functions as a master regulator of key oncogenic pathways and of genes involved in cell adhesion, cancer stem cell (CSC) maintenance and epithelial to mesenchyme transition (EMT). Inhibiting the enzymatic activities of NUDT5 prevents oncosphere formation and precludes the activation of cancer driver genes. These findings highlight NUDT5 as an upstream regulator of tumour drivers and may provide a biomarker for cancer stratification, as well as a novel target for drug discovery for combinatorial drug regimens for the treatment of aggressive cancer types and metastasis.
• dc.description.sponsorship The experimental work mentioned was supported by European Research Council (Project “4D Genome” 609989), the Ministerio de Economía y Competitividad (Project G62426937) and the Generalitat de Catalunya (Project AGAUR SGR 575).
• dc.format.mimetype application/pdf
• dc.identifier.citation Pickup KE, Pardow F, Carbonell-Caballero J, Lioutas A, Villanueva-Cañas JL, Wright RHG, Beato M. Expression of oncogenic drivers in 3D cell culture depends on nuclear ATP synthesis by NUDT5. Cancers (Basel). 2019; 11(9). pii: E1337. DOI: 10.3390/cancers11091337
• dc.identifier.doi http://dx.doi.org/10.3390/cancers11091337
• dc.identifier.issn 2072-6694
• dc.identifier.uri http://hdl.handle.net/10230/43930
• dc.language.iso eng
• dc.publisher MDPI
• dc.relation.ispartof Cancers (Basel). 2019; 11(9). pii: E1337
• dc.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
• dc.rights © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by/4.0/
• dc.subject.keyword 3D cell cultures
• dc.subject.keyword EMT
• dc.subject.keyword Breast cancer
• dc.subject.keyword Cancer stem cell (CSC)
• dc.subject.keyword Metastasis
• dc.subject.keyword Cell–cell communication
• dc.subject.keyword Cytoskeleton
• dc.subject.keyword Motility
• dc.subject.keyword Oncospheres
• dc.subject.keyword Proliferation
• dc.subject.keyword Recurrence
• dc.title Expression of oncogenic drivers in 3D cell culture depends on nuclear ATP synthesis by NUDT5
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion