Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia

Autor: Nareg Pinarbasi-Degirmenci, Ilknur Sur-Erdem, Vuslat Akcay, Yasemin Bolukbasi, Ugur Selek, Ihsan Solaroglu, Tugba Bagci-Onder
Přispěvatelé: Değirmenci, Nareg Pınarbaşı, Erdem, İlknur Sur, Akçay, Vuslat, Bölükbaşı, Yasemin (ORCID 0000-0002-3170-5826 & YÖK ID 216814), Selek, Uğur (ORCID 0000-0001-8087-3140 & YÖK ID 27211), Solaroğlu, İhsan (ORCID 0000-0002-9472-1735 & YÖK ID 102059), Önder, Tuğba Bağcı (ORCID 0000-0003-3646-2613 & YÖK ID 184359), Koç University Research Center for Translational Medicine (KUTTAM) / Koç Üniversitesi Translasyonel Tıp Araştırma Merkezi (KUTTAM), Koç University Hospital, Graduate School of Health Sciences, College of Sciences, School of Medicine, Department of Molecular Biology and Genetics
Rok vydání: 2022
Předmět:
Zdroj: International Journal of Molecular Sciences
International Journal of Molecular Sciences; Volume 23; Issue 13; Pages: 7051
ISSN: 1422-0067
Popis: 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 naive glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naive and IR-Surv cells. However, IR-Surv cells' 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 naive and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.
Scientific and Technological Research Council of Turkey (TÜBİTAK)
Databáze: OpenAIRE
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