Research Project: Glioblastoma Hücrelerinde Kemo-Radyoterapi Direncinin Crispr-Cas9 Aracılı Gen Silme Ve Genom Bazlı Tarama Yöntemleriyle Araştırılması
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Contributors
Funders
ID
TB.00341
Authors
Sur, İlknur Erdem
Faculty Member
Publications
Impact of ferroptosis inducers on chronic radiation-exposed survivor glioblastoma cells
(Bentham Science Publishers, 2023) Sur, İlknur Erdem; KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; Research Center; SCHOOL OF MEDICINE
Introduction: The median survival of patients diagnosed with glioblastoma is very poor, despite efforts to improve the therapeutic effects of surgery, followed by treatment with temozolomide (TMZ) and ionizing radiation (IR). The utilization of TMZ or IR survivor cell models has enhanced the understanding of glioblastoma biology and the development of novel therapeutic strategies. In this present study, naive U373 and clinically relevant U373 IR-survivor (Surv) cells were used, as the IR-Surv cell model mimics the chronic long-term exposure to standardized radiotherapy for patients with glioblastoma in the clinic. As the role of ferroptosis in the IR survivor cell model has not previously been reported, we aimed to clarify its involvement in the clinically relevant IR-Surv glioblastoma model.Methods: Transcriptomic alterations of ferroptosis-related genes were studied on naive U373 and IR-Surv cell populations. To determine the effects of glutathione peroxidase inhibitors, ferroptosis-inducing agent 56 (FIN56) and Ras synthetic lethal 3 (RSL3), on the cells, several properties were assessed, including colony formation, cell viability and lipid peroxidation.Results: Results from the transcriptomic analysis identified ferroptosis as a critical mechanism after radiation exposure in glioblastoma. Our findings also identified the role of ferroptosis inducers (FINs) in IR-survivor cells and suggested using FINs to treat glioblastoma.Conclusion: FINs serve an important role in radioresistant cells; thus, the results of the present study may contribute to improving survival in patients with glioblastoma.
Chronically radiation-exposed survivor glioblastoma cells display poor response to Chk1 inhibition under hypoxia
(Multidisciplinary Digital Publishing Institute (MDPI), 2022) Akçay, Vuslat; Bölükbaşı, Yasemin; Değirmenci, Nareg Pınarbaşı; Önder, Tuğba Bağcı; Selek, Uğur; Solaroğlu, İhsan; Sur, İlknur Erdem; Department of Molecular Biology and Genetics; Graduate School of Health Sciences; KUH (Koç University Hospital); KUTTAM (Koç University Research Center for Translational Medicine); School of Medicine; Yes; College of Sciences; GRADUATE SCHOOL OF HEALTH SCIENCES; KUH (KOÇ UNIVERSITY HOSPITAL); Research Center; SCHOOL OF MEDICINE
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.
