{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,2]],"date-time":"2026-10-02T03:19:15Z","timestamp":1790911155264,"version":"4.1.0"},"reference-count":69,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2022,6,24]],"date-time":"2022-06-24T00:00:00Z","timestamp":1656028800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100004410","name":"Scientific and Technological Research Council of Turkey (TUBITAK)","doi-asserted-by":"publisher","award":["117S043"],"award-info":[{"award-number":["117S043"]}],"id":[{"id":"10.13039\/501100004410","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Presidency of Turkey, Presidency of Strategy and Budget","award":["117S043"],"award-info":[{"award-number":["117S043"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Glioblastoma is the most malignant primary brain tumor, and a cornerstone in its treatment is radiotherapy. However, tumor cells surviving after irradiation indicates treatment failure; therefore, better understanding of the mechanisms regulating radiotherapy response is of utmost importance. In this study, we generated clinically relevant irradiation-exposed models by applying fractionated radiotherapy over a long time and selecting irradiation-survivor (IR-Surv) glioblastoma cells. We examined the transcriptomic alterations, cell cycle and growth rate changes and responses to secondary radiotherapy and DNA damage response (DDR) modulators. Accordingly, IR-Surv cells exhibited slower growth and partly retained their ability to resist secondary irradiation. Concomitantly, IR-Surv cells upregulated the expression of DDR-related genes, such as CHK1, ATM, ATR, and MGMT, and had better DNA repair capacity. IR-Surv cells displayed downregulation of hypoxic signature and lower induction of hypoxia target genes, compared to na\u00efve glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both na\u00efve and IR-Surv cells. However, IR-Surv cells\u2019 response to Chk1 inhibition markedly decreased under hypoxic conditions. Taken together, we demonstrate the utility of combining DDR inhibitors and irradiation as a successful approach for both na\u00efve and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.<\/jats:p>","DOI":"10.3390\/ijms23137051","type":"journal-article","created":{"date-parts":[[2022,6,26]],"date-time":"2022-06-26T09:00:13Z","timestamp":1656234013000},"page":"7051","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia"],"prefix":"10.3390","volume":"23","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3366-145X","authenticated-orcid":false,"given":"Nareg","family":"Pinarbasi-Degirmenci","sequence":"first","affiliation":[{"name":"Brain Cancer Research and Therapy Laboratory, Ko\u00e7 University School of Medicine, Istanbul 34450, Turkey"},{"name":"Research Center for Translational Medicine, Ko\u00e7 University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ilknur","family":"Sur-Erdem","sequence":"additional","affiliation":[{"name":"Brain Cancer Research and Therapy Laboratory, Ko\u00e7 University School of Medicine, Istanbul 34450, Turkey"},{"name":"Research Center for Translational Medicine, Ko\u00e7 University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vuslat","family":"Akcay","sequence":"additional","affiliation":[{"name":"Brain Cancer Research and Therapy Laboratory, Ko\u00e7 University School of Medicine, Istanbul 34450, Turkey"},{"name":"Research Center for Translational Medicine, Ko\u00e7 University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3170-5826","authenticated-orcid":false,"given":"Yasemin","family":"Bolukbasi","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ko\u00e7 University School of Medicine, Istanbul 34010, Turkey"},{"name":"Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8087-3140","authenticated-orcid":false,"given":"Ugur","family":"Selek","sequence":"additional","affiliation":[{"name":"Department of Radiation Oncology, Ko\u00e7 University School of Medicine, Istanbul 34010, Turkey"},{"name":"Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9472-1735","authenticated-orcid":false,"given":"Ihsan","family":"Solaroglu","sequence":"additional","affiliation":[{"name":"Research Center for Translational Medicine, Ko\u00e7 University, Istanbul 34450, Turkey"},{"name":"Department of Neurosurgery, Ko\u00e7 University School of Medicine, Istanbul 34010, Turkey"},{"name":"Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3646-2613","authenticated-orcid":false,"given":"Tugba","family":"Bagci-Onder","sequence":"additional","affiliation":[{"name":"Brain Cancer Research and Therapy Laboratory, Ko\u00e7 University School of Medicine, Istanbul 34450, Turkey"},{"name":"Research Center for Translational Medicine, Ko\u00e7 University, Istanbul 34450, Turkey"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,6,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"381","DOI":"10.1016\/B978-0-12-802997-8.00023-2","article-title":"Glioblastoma","volume":"134","author":"Wirsching","year":"2016","journal-title":"Handb. 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