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Article

Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells

1
Gastrointestinal and Pancreatic Oncology Team, Institut D’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Hospital Clínic de Barcelona, Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), 08036 Barcelona, Spain
2
Section for Cancer Genomics, Genetics Branch, National Cancer Institute, National Institute of Health, Bethesda, MD 20817, USA
3
Department of Medical Biology, Faculty of Medicine, Dokuz Eylul University, 35330 Izmir, Turkey
4
Radiation Oncology Department, Hospital Clínic de Barcelona, 08036 Barcelona, Spain
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Unitat de Biologia Cel·lular i Genètica Mèdica, Departament de Biologia Cel·lular, Fisiologia i Immunologia, Facultat de Medicina, Universitat Autònoma de Barcelona, 08193 Bellaterra, Spain
*
Authors to whom correspondence should be addressed.
Current affiliation for Ö.G.G.: Department of Nutrition and Dietetics, Faculty of Health Sciences, İstinye University, 34010 Istanbul, Turkey.
Cancers 2020, 12(5), 1118; https://doi.org/10.3390/cancers12051118
Received: 18 March 2020 / Revised: 23 April 2020 / Accepted: 27 April 2020 / Published: 30 April 2020
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. View Full-Text
Keywords: tetraploidy; whole-genome duplication; chemotherapy; radiotherapy; drug resistance; colorectal cancer tetraploidy; whole-genome duplication; chemotherapy; radiotherapy; drug resistance; colorectal cancer
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MDPI and ACS Style

Galofré, C.; Gönül Geyik, Ö.; Asensio, E.; Wangsa, D.; Hirsch, D.; Parra, C.; Saez, J.; Mollà, M.; Yüce, Z.; Castells, A.; Ried, T.; Camps, J. Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells. Cancers 2020, 12, 1118. https://doi.org/10.3390/cancers12051118

AMA Style

Galofré C, Gönül Geyik Ö, Asensio E, Wangsa D, Hirsch D, Parra C, Saez J, Mollà M, Yüce Z, Castells A, Ried T, Camps J. Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells. Cancers. 2020; 12(5):1118. https://doi.org/10.3390/cancers12051118

Chicago/Turabian Style

Galofré, Claudia; Gönül Geyik, Öykü; Asensio, Elena; Wangsa, Darawalee; Hirsch, Daniela; Parra, Carolina; Saez, Jordi; Mollà, Meritxell; Yüce, Zeynep; Castells, Antoni; Ried, Thomas; Camps, Jordi. 2020. "Tetraploidy-Associated Genetic Heterogeneity Confers Chemo-Radiotherapy Resistance to Colorectal Cancer Cells" Cancers 12, no. 5: 1118. https://doi.org/10.3390/cancers12051118

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