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Volume 23
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10.3390/ijms23137051
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Article

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

by
Nareg Pinarbasi-Degirmenci
1,2,
Ilknur Sur-Erdem
1,2,*,
Vuslat Akcay
1,2,
Yasemin Bolukbasi
3,4,
Ugur Selek
3,4,
Ihsan Solaroglu
2,5,6 and
Tugba Bagci-Onder
1,2,*
1
Brain Cancer Research and Therapy Laboratory, Koç University School of Medicine, Istanbul 34450, Turkey
2
Research Center for Translational Medicine, Koç University, Istanbul 34450, Turkey
3
Department of Radiation Oncology, Koç University School of Medicine, Istanbul 34010, Turkey
4
Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
5
Department of Neurosurgery, Koç University School of Medicine, Istanbul 34010, Turkey
6
Department of Basic Sciences, Loma Linda University, Loma Linda, CA 92354, USA
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2022, 23(13), 7051; https://doi.org/10.3390/ijms23137051
Submission received: 17 April 2022 / Revised: 30 May 2022 / Accepted: 10 June 2022 / Published: 24 June 2022
(This article belongs to the Special Issue Glioblastoma: Recapitulating the Key Breakthroughs and Future Perspective)
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Abstract

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 naïve glioblastoma cells. Moreover, Chk1 inhibition alone or in combination with irradiation significantly reduced cell viability in both naïve 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 naïve and IR-Surv glioblastoma cells as long as cells are refrained from hypoxic conditions.
Keywords: glioblastoma; radiotherapy; radioresistance; hypoxia; DNA damage response; Chk1 glioblastoma; radiotherapy; radioresistance; hypoxia; DNA damage response; Chk1

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MDPI and ACS Style

Pinarbasi-Degirmenci, N.; Sur-Erdem, I.; Akcay, V.; Bolukbasi, Y.; Selek, U.; Solaroglu, I.; Bagci-Onder, T. Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia. Int. J. Mol. Sci. 2022, 23, 7051. https://doi.org/10.3390/ijms23137051

AMA Style

Pinarbasi-Degirmenci N, Sur-Erdem I, Akcay V, Bolukbasi Y, Selek U, Solaroglu I, Bagci-Onder T. Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia. International Journal of Molecular Sciences. 2022; 23(13):7051. https://doi.org/10.3390/ijms23137051

Chicago/Turabian Style

Pinarbasi-Degirmenci, Nareg, Ilknur Sur-Erdem, Vuslat Akcay, Yasemin Bolukbasi, Ugur Selek, Ihsan Solaroglu, and Tugba Bagci-Onder. 2022. "Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia" International Journal of Molecular Sciences 23, no. 13: 7051. https://doi.org/10.3390/ijms23137051

APA Style

Pinarbasi-Degirmenci, N., Sur-Erdem, I., Akcay, V., Bolukbasi, Y., Selek, U., Solaroglu, I., & Bagci-Onder, T. (2022). Chronically Radiation-Exposed Survivor Glioblastoma Cells Display Poor Response to Chk1 Inhibition under Hypoxia. International Journal of Molecular Sciences, 23(13), 7051. https://doi.org/10.3390/ijms23137051

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