Tetraploidy-associated genetic heterogeneity confers chemo-radiotherapy resistance to colorectal cancer cells

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dc.authoridÖykü Gönül Geyik / 0000-0003-3014-1253en_US
dc.authorscopusidÖykü Gönül Geyik / 56695248800
dc.authorwosidÖykü Gönül Geyik / AHB-4716-2022
dc.contributor.authorGalofré C.
dc.contributor.authorGönül Geyik, Öykü
dc.contributor.authorAsensio E.
dc.contributor.authorWangsa D.
dc.contributor.authorHirsch D.
dc.contributor.authorParra C.
dc.contributor.authorSaez, J.
dc.contributor.authorMollà, Meritxell
dc.contributor.authorYüce, Zeynep
dc.contributor.authorCastells, Antoni
dc.contributor.authorRied, Thomas
dc.contributor.authorCamps, Jordi
dc.date.accessioned2020-08-30T20:01:33Z
dc.date.available2020-08-30T20:01:33Z
dc.date.issued2020
dc.departmentİstinye Üniversitesi, Sağlık Bilimleri Fakültesi, Beslenme ve Diyetetik Bölümüen_US
dc.description.abstractTetraploidy, or whole-genome duplication, is a common phenomenon in cancer and preludes chromosome instability, which strongly correlates with disease progression, metastasis, and treatment failure. Therefore, it is reasonable to hypothesize that tetraploidization confers multidrug resistance. Nevertheless, the contribution of whole-genome duplication to chemo-radiotherapy resistance remains unclear. Here, using isogenic diploid and near-tetraploid clones from three colorectal cancer cell lines and one non-transformed human epithelial cell line, we show a consistent growth impairment but a divergent tumorigenic potential of near-tetraploid cells. Next, we assessed the effects of first-line chemotherapeutic drugs, other commonly used agents and ionizing radiation, and found that whole-genome duplication promoted increased chemotherapy resistance and also conferred protection against irradiation. When testing the activation of apoptosis, we observed that tetraploid cells were less prone to caspase 3 activation after treatment with first-line chemotherapeutic agents. Furthermore, we found that pre-treatment with ataxia telangiectasia and Rad3 related (ATR) inhibitors, which targets response to replication stress, significantly enhanced the sensitivity of tetraploid cells to first-line chemotherapeutic agents as well as to ionizing radiation. Our findings provide further insight into how tetraploidy results in greater levels of tolerance to chemo-radiotherapeutic agents and, moreover, we show that ATR inhibitors can sensitize near-tetraploid cells to commonly used chemo-radiotherapy regimens. © 2020 by the authors. Licensee MDPI, Basel, Switzerland.en_US
dc.description.sponsorshipDeutsche Krebshilfe Generalitat de Catalunya: 2017 SGR 1035 Türkiye Bilimsel ve Teknolojik AraÅŸtirma Kurumu Deutsche Krebshilfe Fundación Científica Asociación Española Contra el Cáncer: GCB13131592CAST European Cooperation in Science and Technology European Regional Development Fund: CPII18/00026, PI14/00783, PI17/01304 European Cooperation in Science and Technology: CA17118 Agència de Gestió d'Ajuts Universitaris i de Recerca Instituto de Salud Carlos IIIen_US
dc.description.sponsorshipFunding: This research was funded by grants from the Instituto de Salud Carlos III and co-funded by the European Regional Development Fund (ERDF) (CPII18/00026, PI14/00783, PI17/01304), the CIBEREHD program, the Agència de Gestió d’Ajuts Universitaris i de Recerca, Generalitat de Catalunya (2017 SGR 1035), and Fundación Científica de la Asociación Española Contra el Cáncer (GCB13131592CAST). CG was supported by a contract from CIBEREHD and GEMCAD. Ö.G.G. was funded by Scientific and Technological Research Council of Turkey (TÜBİTAK) via 2214/A program. D.H. was supported by a Mildred Scheel postdoctoral scholarship of the German Cancer Aid (Deutsche Krebshilfe). This article is based on work from COST Action CA17118, supported by COST (European Cooperation in Science and Technology).en_US
dc.identifier.citationGalofré, C., Gönül Geyik, Ö., Asensio, E., Wangsa, D., Hirsch, D., Parra, C., ... & Ried, T. (2020). Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells. Cancers, 12(5), 1118.en_US
dc.identifier.doi10.3390/cancers12051118en_US
dc.identifier.issn2072-6694en_US
dc.identifier.issue5en_US
dc.identifier.scopus2-s2.0-85084204259en_US
dc.identifier.scopusqualityQ1en_US
dc.identifier.urihttps://doi.org/10.3390/cancers12051118
dc.identifier.urihttps://hdl.handle.net/20.500.12713/286
dc.identifier.volume12en_US
dc.identifier.wosWOS:000539246000059en_US
dc.identifier.wosqualityQ1en_US
dc.indekslendigikaynakWeb of Scienceen_US
dc.indekslendigikaynakScopusen_US
dc.institutionauthorGönül Geyik, Öyküen_US
dc.language.isoenen_US
dc.publisherMDPI AGen_US
dc.relation.ispartofCancersen_US
dc.relation.publicationcategoryMakale - Uluslararası Hakemli Dergi - Kurum Öğretim Elemanıen_US
dc.rightsinfo:eu-repo/semantics/openAccessen_US
dc.subjectChemotherapyen_US
dc.subjectColorectal Canceren_US
dc.subjectDrug Resistanceen_US
dc.subjectRadiotherapyen_US
dc.subjectTetraploidyen_US
dc.subjectWhole-Genome Duplicationen_US
dc.titleTetraploidy-associated genetic heterogeneity confers chemo-radiotherapy resistance to colorectal cancer cellsen_US
dc.typeArticleen_US

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