Tetraploidy-associated genetic heterogeneity confers chemo-radiotherapy resistance to colorectal cancer cells
Galofré, Claudia (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Gönül Geyik, Öykü (Dokuz Eylul University. Department of Medical Biology)
Asensio, Elena (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Wangsa, Darawalee (National Institute of Health (Bethesda, EUA))
Hirsch, Daniela (National Institute of Health (Bethesda, EUA))
Parra, Carolina (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Saez, Jordi (Hospital Clínic i Provincial de Barcelona)
Mollà, Meritxell (Hospital Clínic i Provincial de Barcelona)
Yüce, Zeynep (Dokuz Eylul University. Department of Medical Biology)
Castells, Antoni (Institut d'Investigacions Biomèdiques August Pi i Sunyer)
Ried, Thomas (National Institute of Health (Bethesda, EUA))
Camps, Jordi (Universitat Autònoma de Barcelona. Departament de Biologia Cel·lular, de Fisiologia i d'Immunologia)

Data:	2020
Resum:	Tetraploidy, 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.
Ajuts:	Instituto de Salud Carlos III CPII18/00026 Instituto de Salud Carlos III PI14/00783 Instituto de Salud Carlos III PI17/01304 Agència de Gestió d'Ajuts Universitaris i de Recerca 2017/SGR-1035
Nota:	Altres ajuts: 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).
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	Tetraploidy ; Whole-genome duplication ; Chemotherapy ; Radiotherapy ; Drug resistance ; Colorectal cancer
Publicat a:	Cancers, Vol. 12, issue 5 (May 2020) , art. 1118, ISSN 2072-6694

DOI: 10.3390/cancers12051118
PMID: 32365785

15 p, 2.1 MB

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