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A novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genes

2014-12-09Journal article Open access
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dc.contributor.authorHill, Richard
dc.contributor.authorKalathur, Ravi Kiran Reddy
dc.contributor.authorCallejas, Sergio
dc.contributor.authorColaço, Laura
dc.contributor.authorBrandão, Ricardo
dc.contributor.authorSerelde, Beatriz
dc.contributor.authorCebriá, Antonio
dc.contributor.authorBlanco-Aparicio, Carmen
dc.contributor.authorPastor, Joaquín
dc.contributor.authorFutschik, Matthias
dc.contributor.authorDopazo, Ana
dc.contributor.authorLink, Wolfgang
dc.date.accessioned2015-05-06T10:33:14Z
dc.date.available2015-05-06T10:33:14Z
dc.date.issued2014-12-09
dc.date.updated2015-01-19T20:25:57Z
dc.description.abstractIntroduction: The activation of the phosphoinositide 3-kinase (PI3K)/AKT signalling pathway is one the most frequent genetic events in breast cancer, consequently the development of PI3K inhibitors has attracted much attention. Here we evaluate the effect of PI3K inhibition on global gene expression in breast cancer cells. Methods: We used a range of methodologies that include in silico compound analysis, in vitro kinase assays, cell invasion assays, proliferation assays, genome-wide transcription studies (Agilent Technologies full genome arrays), gene set enrichment analysis, quantitative real-time PCR, immunoblotting in addition to chromatin immunoprecipitation. Results: We defined the physico-chemical and the biological properties of ETP-45658, a novel potent PI3K inhibitor. We demonstrated that ETP-45658 potently inhibited cell proliferation within a broad range of human cancer cells, most potently suppressing the growth of breast cancer cells via inhibiting cell cycle. We show that this response is Forkhead box O (FOXO) protein dependent and p53 independent. Our genome-wide microarray analysis revealed that the cell cycle was the most affected biological process after exposure to ETP-45658 (or our control PI3K inhibitor PI-103), that despite the multiple transcription factors that are regulated by the PI3K/AKT signalling cascade, only the binding sites for FOXO transcription factors were significantly enriched and only a subset of all FOXO-dependent genes were induced. This disparity in gene transcription was not due to differential FOXO promoter recruitment. Conclusions: The constitutive activation of PI3Ks and thus the exclusion of FOXO transcription factors from the nucleus is a key feature of breast cancer. Our results presented here highlight that PI3K inhibition activates specific FOXO-dependent genes that mediate cell cycle arrest in breast cancer cells.por
dc.identifier.citationBreast Cancer Research. 2014 Dec 09;16(6):482por
dc.identifier.doihttp://dx.doi.org/10.1186/s13058-014-0482-y
dc.identifier.urihttp://hdl.handle.net/10400.1/5997
dc.language.isoporpor
dc.peerreviewedyespor
dc.publisherBioMed Centralpor
dc.rights.holderRichard Hill et al.; licensee BioMed Central Ltd.
dc.titleA novel phosphatidylinositol 3-kinase (PI3K) inhibitor directs a potent FOXO-dependent, p53-independent cell cycle arrest phenotype characterized by the differential induction of a subset of FOXO-regulated genespor
dc.typejournal article
dspace.entity.typePublication
oaire.citation.issue6:482por
oaire.citation.titleBreast Cancer Researchpor
oaire.citation.volume16por
person.familyNameHill
person.familyNameKalathur
person.familyNameBrandão
person.familyNameFutschik
person.familyNameLink
person.givenNameRichard
person.givenNameRavi Kiran Reddy
person.givenNameRicardo
person.givenNameMatthias
person.givenNameWolfgang
person.identifier803637
person.identifier.ciencia-idA71B-AD01-3501
person.identifier.ciencia-id6910-952E-242A
person.identifier.orcid0000-0003-0394-6048
person.identifier.orcid0000-0003-2894-3345
person.identifier.orcid0000-0002-0815-1597
person.identifier.orcid0000-0002-6245-8071
person.identifier.orcid0000-0002-3340-5165
person.identifier.scopus-author-id55266604200
person.identifier.scopus-author-id22940879800
person.identifier.scopus-author-id14017989400
person.identifier.scopus-author-id35368713800
rcaap.rightsopenAccesspor
rcaap.typearticlepor
relation.isAuthorOfPublicatione67f4a4f-aa35-4740-87b0-0cd07a9e1993
relation.isAuthorOfPublication029974a3-d5b1-48f5-a44c-ca866e556336
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relation.isAuthorOfPublication.latestForDiscoveryae124994-140a-4a7c-824b-3e75899a084b

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