Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells

Sun, Chao; Wang, Zhongyong; Song, Wu-chao; Chen, Baomin; Zhang, Jinshi; Wang, Lin; Wu, Jinding; Lan, Qing; Huang, Qiang; Dong, Jun

doi:10.3892/ol.2015.3411

Cited by 8 publications

(5 citation statements)

References 23 publications

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“…XPA was over-expressed in radioresistant cells, but under-expressed in radiosensitive cells in response to irradiation. This was also observed in radioresistant glioblastoma cells [64]. The increased expression of XPA , and consequently activated NER could be associated with cross-resistance to CDDP, observed in radioresistant cells.…”

Section: Discussionmentioning

confidence: 78%

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

et al. 2019

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Background: Treatment options for recurrent head and neck tumours in the previously irradiated area are limited, including re-irradiation due to radioresistance of the recurrent tumour and previous dose received by surrounding normal tissues. As an in vitro model to study radioresistance mechanisms, isogenic cells with different radiosensitivity can be used. However, they are not readily available. Therefore, our objective was to establish and characterize radioresistant isogenic human pharyngeal squamous carcinoma cells and to evaluate early radiation response in isogenic parental, radioresistant and radiosensitive cells. Methods: Radioresistant cells were derived from parental FaDu cells by repeated exposure to ionizing radiation. Radiosensitivity of the established isogenic radioresistant FaDu-RR cells was evaluated by clonogenic assay and compared to isogenic parental FaDu and radiosensitive 2A3 cells. Additional phenotypic characterization of these isogenic cells with different radiosensitivity included evaluation of chemosensitivity, cell proliferation, cell cycle, radiation-induced apoptosis, resolution of DNA double-strand breaks, and DNA damage and repair signalling gene expression before and after irradiation. Results: In the newly established radioresistant cells in response to 5 Gy irradiation, we observed no alteration in cell cycle regulation, but delayed induction and enhanced resolution of DNA double-strand breaks, lower induction of apoptosis, and pronounced over-expression of DNA damage signalling genes in comparison to parental cells. On the other hand, radiosensitive 2A3 cells were arrested in G 2 /M-phase in response to 5 Gy irradiation, had a prominent accumulation of and slower resolution of DNA double-strand breaks, and no change in DNA damage signalling genes expression. Conclusions: We concluded that the emergence of the radioresistance in the established radioresistant isogenic cells can be at least partially attributed to the enhanced DNA double-strand break repair, altered expression of DNA damage signalling and repair genes. On the other hand, in radiosensitive isogenic cells the reduced ability to repair a high number of induced DNA double-strand breaks and no transcriptional response in DNA damage signalling genes indicate on a lack of adaptive response to irradiation. Altogether, our results confirmed that these isogenic cells with different radiosensitivity are an appropriate model to study the mechanisms of radioresistance.

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Section: Discussionmentioning

confidence: 78%

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

et al. 2019

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“…9). Of note, PPP1R15A, a gene implicated in DDR and cellular stress 38 , was transcriptionally induced only in stimulated WT1 neurons (Suppl. Table 4).…”

Section: Resultsmentioning

confidence: 99%

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

Corti

Sota

Dugo

et al. 2019

Sci Rep

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Ataxia Telangiectasia (A-T) is neurodegenerative syndrome caused by inherited mutations inactivating the ATM kinase, a master regulator of the DNA damage response (DDR). What makes neurons vulnerable to ATM loss remains unclear. In this study we assessed on human iPSC-derived neurons whether the abnormal accumulation of DNA-Topoisomerase 1 adducts (Top1ccs) found in A-T impairs transcription elongation, thus favoring neurodegeneration. Furthermore, whether neuronal activity-induced immediate early genes (IEGs), a process involving the formation of DNA breaks, is affected by ATM deficiency. We found that Top1cc trapping by CPT induces an ATM-dependent DDR as well as an ATM-independent induction of IEGs and repression especially of long genes. As revealed by nascent RNA sequencing, transcriptional elongation and recovery were found to proceed with the same rate, irrespective of gene length and ATM status. Neuronal activity induced by glutamate receptors stimulation, or membrane depolarization with KCl, triggered a DDR and expression of IEGs, the latter independent of ATM. In unperturbed A-T neurons a set of genes (FN1, DCN, RASGRF1, FZD1, EOMES, SHH, NR2E1) implicated in the development, maintenance and physiology of central nervous system was specifically downregulated, underscoring their potential involvement in the neurodegenerative process in A-T patients.

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“…After one week during which the medium was not replaced, the cells without any treatment, and cells treated with DMSO and ZnCl 2 formed aggregates tending to sphere formation ( Supplementary Figure S3 ). Sphere forming cells are referred to as glioblastoma stem-like cells (GSLCs) demonstrating improved survival subsequent to irradiation and chemotherapy and contribute to the recurrence of GBM [ 26 ]. These aggregates were inhibited by both the TMZ and the combination treatment but cells in the TMZ arm are enlarged, as in senescence, and the cells with combination treatment are smaller as cells appear before apoptosis as can be seen in the Supplementary Figure S3 .…”

Section: Resultsmentioning

confidence: 99%

Zinc enhances temozolomide cytotoxicity in glioblastoma multiforme model systems

et al. 2016

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Temozolomide (TMZ) is an alkylating agent that has become the mainstay treatment of the most malignant brain cancer, glioblastoma multiforme (GBM). Unfortunately only a limited number of patients positively respond to it. It has been shown that zinc metal reestablishes chemosensitivity but this effect has not been tested with TMZ. Using both in vitro and in vivo experimental approaches, we investigated whether addition of zinc to TMZ enhances its cytotoxicity against GBM. In vitro cell viability analysis showed that the cytotoxic activity of TMZ was substantially increased with addition of zinc and this response was accompanied by an elevation of p21, PUMA, BAX and Caspase-3 expression and a decrease in growth fraction as manifested by low ki67 and lower colony formation. Analysis of GBM as intracranial xenografts in athymic mice and administration of concurrent TMZ and zinc yielded results consistent with those of the in vitro analyses. The co-treatment resulted in significant reduction in tumor volume in TMZ/zinc treated mice relative to treatment with TMZ alone. Our results suggest that zinc may serve as a potentiator of TMZ therapy in GBM patients.

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Alteration of DNA damage signaling pathway profile in radiation-treated glioblastoma stem-like cells

Cited by 8 publications

References 23 publications

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

Mechanisms of different response to ionizing irradiation in isogenic head and neck cancer cell lines

DNA damage and transcriptional regulation in iPSC-derived neurons from Ataxia Telangiectasia patients

Zinc enhances temozolomide cytotoxicity in glioblastoma multiforme model systems

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