Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models

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dc.contributor.authorPhelan, John P.
dc.contributor.authorReen, F. Jerry
dc.contributor.authorDunphy, Niall
dc.contributor.authorO'Connor, Rosemary
dc.contributor.authorO'Gara, Fergal
dc.contributor.funderScience Foundation Irelanden
dc.contributor.funderDepartment of Agriculture, Food and the Marineen
dc.contributor.funderIrish Research Council for Science, Engineering and Technologyen
dc.contributor.funderHealth Research Boarden
dc.contributor.funderMarine Instituteen
dc.contributor.funderTeagascen
dc.contributor.funderSeventh Framework Programmeen
dc.date.accessioned2016-10-18T09:10:17Z
dc.date.available2016-10-18T09:10:17Z
dc.date.issued2016-07-14
dc.description.abstractBACKGROUND: The role of the microbiome has become synonymous with human health and disease. Bile acids, as essential components of the microbiome, have gained sustained credibility as potential modulators of cancer progression in several disease models. At physiological concentrations, bile acids appear to influence cancer phenotypes, although conflicting data surrounds their precise physiological mechanism of action. Previously, we demonstrated bile acids destabilised the HIF-1α subunit of the Hypoxic-Inducible Factor-1 (HIF-1) transcription factor. HIF-1 overexpression is an early biomarker of tumour metastasis and is associated with tumour resistance to conventional therapies, and poor prognosis in a range of different cancers. METHODS: Here we investigated the effects of bile acids on the cancer growth and migratory potential of cell lines where HIF-1α is known to be active under hypoxic conditions. HIF-1α status was investigated in A-549 lung, DU-145 prostate and MCF-7 breast cancer cell lines exposed to bile acids (CDCA and DCA). Cell adhesion, invasion, migration was assessed in DU-145 cells while clonogenic growth was assessed in all cell lines. RESULTS: Intracellular HIF-1α was destabilised in the presence of bile acids in all cell lines tested. Bile acids were not cytotoxic but exhibited greatly reduced clonogenic potential in two out of three cell lines. In the migratory prostate cancer cell line DU-145, bile acids impaired cell adhesion, migration and invasion. CDCA and DCA destabilised HIF-1α in all cells and significantly suppressed key cancer progression associated phenotypes; clonogenic growth, invasion and migration in DU-145 cells. CONCLUSIONS: These findings suggest previously unobserved roles for bile acids as physiologically relevant molecules targeting hypoxic tumour progression.en
dc.description.sponsorshipScience Foundation Ireland (SSPC-2, 12/RC/2275; 13/TIDA/B2625; 12/TIDA/B2411; 12/TIDA/B2405; 14/TIDA/2438); Department of Agriculture and Food (FIRM/RSF/CoFoRD; FIRM 08/RDC/629; FIRM 1/F009/MabS; FIRM 13/F/516); Irish Research Council for Science, Engineering and Technology (PD/2011/2414; GOIPG/2014/647); Health Research Board/Irish Thoracic Society (MRCG-2014-6); Marine Institute (Beaufort award C2CRA 2007/082); Teagasc (Walsh Fellowship 2013)en
dc.description.statusPeer revieweden
dc.description.versionPublished Versionen
dc.format.mimetypeapplication/pdfen
dc.identifier.articleid476
dc.identifier.citationPhelan, J.P., Reen, F.J., Dunphy, N., O’Connor, R. and O’Gara, F. (2016) 'Bile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell models', BMC Cancer, 16(1), 476 (12 pp.). doi: 10.1186/s12885-016-2528-2en
dc.identifier.doi10.1186/s12885-016-2528-2
dc.identifier.issn1471-2407
dc.identifier.issued1en
dc.identifier.journaltitleBMC Canceren
dc.identifier.urihttps://hdl.handle.net/10468/3190
dc.identifier.volume16en
dc.language.isoenen
dc.publisherBioMed Centralen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/607786/EU/BluePharmTrain/BLUEPHARMTRAINen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/312184/EU/Increasing Value and Flow in the Marine Biodiscovery Pipeline/PHARMASEAen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/311975/EU/Marine Microorganisms: Cultivation Methods for Improving their Biotechnological Applications/MACUMBAen
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP1::KBBE/287589/EU/Marine Microbial Biodiversity, Bioinformatics and Biotechnology/MICRO B3en
dc.relation.projectinfo:eu-repo/grantAgreement/EC/FP7::SP3::PEOPLE/256596/EU/Dissecting the role of a novel transcriptional regulator in microbial-host interactomes./MEXT REGULATIONen
dc.rights© 2016, the Authors. Open Access. This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.en
dc.rights.urihttp://creativecommons.org/licenses/by/4.0/en
dc.subjectBile acidsen
dc.subjectCancer modelsen
dc.subjectDimethyloxaloglycine (DMOG)en
dc.subjectHIF-1 transcription factoren
dc.subjectHIF-1α subuniten
dc.subjectHypoxiaen
dc.titleBile acids destabilise HIF-1α and promote anti-tumour phenotypes in cancer cell modelsen
dc.typeArticle (peer-reviewed)en
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