ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation

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dc.contributorLCC - Laboratório de Ciclo Celularpt_BR
dc.contributor.authorGomes, Luciana Rodriguespt_BR
dc.contributor.authorRocha, Clarissa Ribeiro Reilypt_BR
dc.contributor.authorMartins, Davi Jardimpt_BR
dc.contributor.authorFiore, Ana Paula Zen Petiscopt_BR
dc.contributor.authorKinker, Gabriela Sartipt_BR
dc.contributor.authorBruni-Cardoso, Alexandrept_BR
dc.contributor.authorMenck, Carlos Frederico Martinspt_BR
dc.date.accessioned2020-07-09T21:24:21Z-
dc.date.available2020-07-09T21:24:21Z-
dc.date.issued2019pt_BR
dc.identifier.citationGomes LR, Rocha CRR, Martins DJ, Fiore APZP, Kinker GS, Bruni-Cardoso A, et al. ATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulation. Cell death dis. 2019 June;10:459. doi:10.1038/s41419-019-1689-8.pt_BR
dc.identifier.urihttps://repositorio.butantan.gov.br/handle/butantan/2776-
dc.description.abstractTissue architecture and cell–extracellular matrix (cell–ECM) interaction determine the organ specificity; however, the influences of these factors on anticancer drugs preclinical studies are highly neglected. For considering such aspects, three-dimensional (3D) cell culture models are relevant tools for accurate analysis of cellular responses to chemotherapy. Here we compared the MCF-7 breast cancer cells responses to cisplatin in traditional two-dimensional (2D) and in 3D-reconstituted basement membrane (3D-rBM) cell culture models. The results showed a substantial increase of cisplatin resistance mediated by 3D microenvironment. This phenotype was independent of p53 status and autophagy activity and was also observed for other cellular models, including lung cancer cells. Such strong decrease on cellular sensitivity was not due to differences on drug-induced DNA damage, since similar levels of ?-H2AX and cisplatin–DNA adducts were detected under both conditions. However, the processing of these cisplatin-induced DNA lesions was very different in 2D and 3D cultures. Unlike cells in monolayer, cisplatin-induced DNA damage is persistent in 3D-cultured cells, which, consequently, led to high senescence induction. Moreover, only 3D-cultured cells were able to progress through S cell cycle phase, with unaffected replication fork progression, due to the upregulation of translesion (TLS) DNA polymerase expression and activation of the ATR-Chk1 pathway. Co-treatment with VE-821, a pharmacological inhibitor of ATR, blocked the 3D-mediated changes on cisplatin response, including low sensitivity and high TLS capacity. In addition, ATR inhibition also reverted induction of REV3L by cisplatin treatment. By using REV3L-deficient cells, we showed that this TLS DNA polymerase is essential for the cisplatin sensitization effect mediated by VE-821. Altogether, our results demonstrate that 3D-cell architecture-associated resistance to cisplatin is due to an efficient induction of REV3L and TLS, dependent of ATR. Thus co-treatment with ATR inhibitors might be a promising strategy for enhancement of cisplatin treatment efficiency in breast cancer patients.pt_BR
dc.description.sponsorshipFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)pt_BR
dc.description.sponsorshipCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)pt_BR
dc.description.sponsorshipConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)pt_BR
dc.format.extent459pt_BR
dc.language.isoEnglishpt_BR
dc.relation.ispartofCell Death & Diseasept_BR
dc.rightsOpen Accesspt_BR
dc.titleATR mediates cisplatin resistance in 3D-cultured breast cancer cells via translesion DNA synthesis modulationpt_BR
dc.typeArticlept_BR
dc.identifier.doi10.1038/s41419-019-1689-8pt_BR
dc.identifier.urlhttps://doi.org/10.1038/s41419-019-1689-8pt_BR
dc.contributor.externalUniversidade de São Paulo (USP)¦¦Brasilpt_BR
dc.identifier.citationvolume10pt_BR
dc.subject.keywordBreast cancerpt_BR
dc.subject.keywordCancer microenvironmentpt_BR
dc.subject.keywordDNA damage checkpointspt_BR
dc.subject.keywordMechanisms of diseasept_BR
dc.relation.ispartofabbreviatedCell death dispt_BR
dc.identifier.citationabntv. 10, 459, jun. 2019pt_BR
dc.identifier.citationvancouver2019 June;10:459pt_BR
dc.contributor.butantanGomes, Luciana Rodrigues|:Aluno|:LCC - Laboratório de Ciclo Celular|:PrimeiroAutor:Autor de correspondênciapt_BR
dc.sponsorship.butantanConselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq)¦¦pt_BR
dc.sponsorship.butantanCoordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)¦¦pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/15982-6pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2013/08028pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2011/50856-3pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/10492-0pt_BR
dc.sponsorship.butantanFundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP)¦¦2014/25832-1pt_BR
dc.identifier.bvsccBR78.1pt_BR
dc.identifier.bvsdbIBProdpt_BR
dc.description.dbindexedYespt_BR
item.openairetypeArticle-
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item.grantfulltextembargo_29990101-
item.languageiso639-1English-
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