A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

Lim, Yi Chieh; Roberts, Tara L.; Day, Bryan W.; Harding, Angus; Kozlov, Sergei; Kijas, Amanda W.; Ensbey, Kathleen S.; Walker, David G.; Lavin, Martin F.

doi:10.1158/1535-7163.mct-11-1044

Cited by 82 publications

(58 citation statements)

References 44 publications

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“…In another report, although CD133+ glioma stem cells were shown to display elongated cell cycle and enhanced basal activation of Chk1 and Chk2, neither BER nor SSB repair was found to be increased in CD133+ compared to CD133-glioma cells [45] . Interestingly, Lim et al [46] reported a more efficient HR repair in GICs, but neither a extended cell cycle nor augmented activation of checkpoint proteins was observed in these cells. The reduced DDR was also reported in other CSCs.…”

Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 95%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

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The identification of cancer stem cells (CSCs) that are responsible for tumor initiation, growth, metastasis, and therapeutic resistance might lead to a new thinking on cancer treatments. Similar to stem cells, CSCs also display high resistance to radiotherapy and chemotherapy with genotoxic agents. Thus, conventional therapy may shrink the tumor volume but cannot eliminate cancer. Eradiation of CSCs represents a novel therapeutic strategy. CSCs possess a highly efficient DNA damage response (DDR) system, which is considered as a contributor to the resistance of these cells from exposures to DNA damaging agents. Targeting of enhanced DDR in CSCs is thus proposed to facilitate the eradication of CSCs by conventional therapeutics. To achieve this aim, a better understanding of the cellular responses to DNA damage in CSCs is needed. In addition to the protein kinases and enzymes that are involved in DDR, other processes that affect the DDR including chromatin remodeling should also be explored.

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Section: Activation Of Cell Cycle Checkpoint Machinerymentioning

confidence: 95%

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

Wang

2015

WJBC

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“…Recent studies have extensively investigated the cellular and genetic mechanisms underlying glioblastoma progression (4,5). Although the molecular mechanisms underlying glioma radioresistance have yet to be elucidated, they are thought to involve dysregulated gene expression (6).…”

Section: Introductionmentioning

confidence: 99%

MicroRNA-128a, BMI1 polycomb ring finger oncogene, and reactive oxygen species inhibit the growth of U-87 MG glioblastoma cells following exposure to X-ray radiation

Wang

et al. 2015

Molecular Medicine Reports

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Abstract.Radiotherapy is an important therapeutic strategy for the treatment of numerous types of malignant tumors, including glioma. However, radioresistance and anti-apoptotic mechanisms decrease the efficacy of radiotherapy in many patients with glioma. BMI1 polycomb ring finger oncogene (Bmi-1) is an oncogene associated with radioresistance in tumor cells. MicroRNA (miRNA)-128a is a brain-specific miRNA, which suppresses Bmi-1 expression. The present study investigated the effects of various radiation intensities on U-87 MG glioma cells, as well as the role of reactive oxygen species (ROS), Bmi-1, and miRNA-128a in the cellular response to radiotherapy. The response of U-87 MG cells following exposure to X-ray radiation was assessed using a cell growth curve and inhibition ratio. Cell cycle distribution and the levels of intracellular ROS were evaluated by flow cytometry. The mRNA expression levels of Bmi-1 and those of miRNA-128a in U-87 MG cells exposed to X-ray radiation were evaluated by reverse transcription-quantitative polymerase chain reaction. X-ray radiation did not decrease the number of U-87 MG cells; however, it did inhibit cellular growth in a dose-dependent manner. Following exposure to X-ray radiation for 24 h, cell cycle distribution was altered, with an increase in the number of cells in G 0 /G 1 phase. The mRNA expression levels of Bmi-1 were downregulated in the 1 and 2 Gy groups, and upregulated in the 6 and 8 Gy groups. The expression levels of miRNA-128a were upregulated in the 1 and 2 Gy groups, and downregulated in the 8 Gy group. The levels of ROS were increased following exposure to ≥2 Gy, and treatment with N-acetyl cysteine was able to induce radioresistance. These results suggested that U-87 MG cells exhibited radioresistance. High doses of X-ray radiation increased the expression levels of Bmi-1, which may be associated with the evasion of cellular senescence. miRNA-128a and its downstream target gene Bmi-1 may have an important role in the radioresistance of U-87 MG glioma cells. In addition, ROS may be involved in the mechanisms underlying the inhibitory effects of X-ray radiation in U-87 MG cells, and the downregulation of ROS may induce radioresistance.

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“…In metastatic brain tumors,the expression levels of phosphorylatedChk1 proteins tend to be higher in radioresistant cancer than in radiosensitive cell lines (Seol et al, 2011). Lim et al have proved that cell-cycle checkpoint abnormalities may contribute to the radioresistance of glioma-initiating cells and may be suitable targets for therapy (Lim et al, 2012). The cell cycle division cycle 25 (Cdc25) protein phosphates, including three family proteins, Cdc25a, Cdc25b, Cdc25c, are critical components of cell engine that function to drive cell cycle transitions by dephosphorylating and activating cyclin-dependent kinases (Cdks) (Lee et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Involvement of Cdc25c in Cell Cycle Alteration of a Radioresistant Lung Cancer Cell Line Established with Fractionated Ionizing Radiation

Li¹,

Yang²,

Mei³

et al. 2013

Asian Pacific Journal of Cancer Prevention

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Cancer patients often suffer from local tumor recurrence after radiation therapy. Cell cycling, an intricate sequence of events which guarantees high genomic fidelity, has been suggested to affect DNA damage responses and eventual radioresistant characteristics of cancer cells. Here, we established a radioresistant lung cancer cell line, A549R , by exposing the parental A549 cells to repeated γ-ray irradiation with a total dose of 60 Gy. The radiosensitivity of A549 and A549R was confirmed using colony formation assays. We then focused on examination of the cell cycle distribution between A549 and A549R and found that the proportion of cells in the radioresistant S phase increased, whereas that in the radiosensitive G1 phase decreased. When A549 and A549R cells were exposed to 4 Gy irradiation the total differences in cell cycle redistribution suggested that G2-M cell cycle arrest plays a predominant role in mediating radioresistance. In order to further explore the possible mechanisms behind the cell cycle related radioresistance, we examined the expression of Cdc25 proteins which orchestrate cell cycle transitions. The results showed that expression of Cdc25c increased accompanied by the decrease of Cdc25a and we proposed that the quantity of Cdc25c, rather than activated Cdc25c or Cdc25a, determines the radioresistance of cells.

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A Role for Homologous Recombination and Abnormal Cell-Cycle Progression in Radioresistance of Glioma-Initiating Cells

Cited by 82 publications

References 44 publications

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

DNA damage responses in cancer stem cells: Implications for cancer therapeutic strategies

MicroRNA-128a, BMI1 polycomb ring finger oncogene, and reactive oxygen species inhibit the growth of U-87 MG glioblastoma cells following exposure to X-ray radiation

Involvement of Cdc25c in Cell Cycle Alteration of a Radioresistant Lung Cancer Cell Line Established with Fractionated Ionizing Radiation

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