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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.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.issn 2072-6694
dc.identifier.uri http://hdl.handle.net/10230/43930
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.language.iso eng
dc.publisher MDPI
dc.relation.ispartof Cancers (Basel). 2019; 11(9). pii: E1337
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.uri http://creativecommons.org/licenses/by/4.0/
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.identifier.doi http://dx.doi.org/10.3390/cancers11091337
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.relation.projectID info:eu-repo/grantAgreement/EC/FP7/609989
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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