Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas

Squatrito, Massimo; Brennan, Cameron; Helmy, Karim Y.; Huse, Jason T.; Petrini, John H.J.; Holland, Eric C.

doi:10.1016/j.ccr.2010.10.034

Cited by 215 publications

(184 citation statements)

References 57 publications

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“…This limited, delayed apoptosis in response to IR contrasts sharply with the high levels of apoptosis observed in the more radiosensitive medulloblastoma brain tumor (9). Previous experiments demonstrated that this radiation dose confers only a modest survival benefit of ∼15 d in this model, consistent with the radioresistant phenotype of human GBM and the comparatively minimal apoptosis observed in these experiments (21).…”

Section: Resultsmentioning

confidence: 53%

“…We chose to use a single dose of radiation to enable time course studies after radiation, and had previously shown that a single dose of 10-Gy radiation induces cell cycle arrest in these tumors (21). Tumor-bearing mice were subjected to a single dose of 10-Gy total body ionizing radiation (IR), and tumor tissue was collected at time points after treatment for immunohistochemical staining.…”

Section: Resultsmentioning

confidence: 99%

“…To confirm p53 regulation of specific transcripts, we used irradiated and unirradiated p53 −/− tumorspheres as in ref. 21 and performed qPCR for the same panel of genes as in SI Appendix, Fig. S4 A and B.…”

Section: Ir-induced Changes In Gene Expression Primarily Involve Genementioning

confidence: 99%

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In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Halliday

Helmy

Pattwell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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159

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Significance Glioblastoma is one of the most radio-resistant tumors, and the mechanisms of radioresistance are intensely studied. Here, we use a mouse model of proneural glioma to evaluate in vivo radiation-induced gene expression regulation at both the translational and transcriptional levels. We found that p53 and E2F are major regulators of the in vivo radiation response, and that there is little contribution from translational regulation, in contrast to previous in vitro reports. We also found that radiation induces a rapid shift in subtype from proneural to mesenchymal, which may have important implications for attempts to tailor targeted therapy regimens to tumor subtype.

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Section: Resultsmentioning

confidence: 53%

Section: Resultsmentioning

confidence: 99%

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In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Halliday

Helmy

Pattwell

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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159

161

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“…Loss of heterozygosity has been found in several chromosomes in patients with glioma using molecular analysis. Many of these chromosomal segments contain known tumor-suppressor genes (17,18), such as p16 on 9p, p53 on 17p and RB on 13q. More recently, SLC22A18 was located within the 11p15.5 cluster, and has been assigned a number of different nomenclatures (4,5).…”

Section: Discussionmentioning

confidence: 99%

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Chu

Feng

et al. 2011

Mol Med Report

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Abstract. SLC22A18 [solute carrier family 22 (organic cation transporter) member 18] is located within the 11p15.5 cluster, and may be a new tumor suppressor gene; evidence of SLC22A18 hypermethylation is documented in several types of human cancers. In order to determine whether SLC22A18 hypermethylation is involved in glioma, we determined the SLC22A18 gene protein expression, mRNA expression and methylation status in glioma U251 cells before and after treatment with 5-Aza-2'-deoxycytidine (5-Aza-CdR), and observed the change in growth. Glioma U251 cells treated with 5-AzaCdR were analyzed by flow cytometry to identify any change in their cell cycle profiles. Tumors induced via the injection of untreated U251 cells were measured. Immunohistochemistry, reverse transcriptase-polymerase chain reaction (RT-PCR) and PCR-based methylation assay were carried out to determine SLC22A18 gene protein expression, mRNA expression and methylation status in glioma U251 cells before and after treatment with 5-Aza-CdR. The treated cells showed an increase in their proportion in G1, from 79.2 to 83.5%, and a decrease in S phase, from 12.4 to 5.8%. The apoptotic rate increased from 6.4 to 15.8%. Tumors induced via the injection of untreated U251 cells were approximately 1.46 cm 3 in size, whereas the tumors induced by U251 cells treated with 5-Aza-CdR averaged 0.88 cm 3 in size. The expression levels of SLC22A18 protein and mRNA in U251 cells were increased following treatment with 5x10 -7 M 5-Aza-CdR. Prior to 5-Aza-CdR treatment, the SLC22A18 gene demonstrated hypermethylation and therefore could not be cleaved by HpaII and MspI. It is known that only the DNA digested with HpaII or MspI can be amplified. Following treatment with 5-Aza-CdR, the SLC22A18 gene became demethylated, and could then be cleaved by both of the enzymes, and this failed to be amplified. 5-Aza-cdR may induce glioma U251 cell division and apoptosis and enhance demethylation and protein and mRNA expression of SLC22A18. The hypermethylation of SLC22A18 may be related to the transcriptional silencing of this gene. The growth inhibitory effects of 5-Aza-CdR treatment in vivo remain recognizable.

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“…Compared to non stem-like glioma cells, the GSCs have higher activity of cell cycle checkpoints (Bao et al 2006). Therefore, GSCs are more resistant to radiation therapy than differentiated tumor cells (Bao et al 2006;Squatrito et al 2010). GSCs represent a small subpopulation of GBM cells, with the stem-like properties and the capacity of multi-lineage differentiation, self-renewal and exact recapitulation of the original tumor.…”

mentioning

confidence: 99%

Knockdown of Checkpoint Kinase 1 Is Associated with the Increased Radiosensitivity of Glioblastoma Stem-Like Cells

Lai

Wan

et al. 2012

Tohoku J. Exp. Med.

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Glioblastoma multiforme is an aggressive brain tumor with a poor prognosis. The glioblastoma stem-like cells (GSCs) represent a rare fraction of human glioblastoma cells with the capacity for multi-lineage differentiation, self-renewal and exact recapitulation of the original tumor. Interestingly, GSCs are more radioresistant compared with other tumor cells. In addition, the remarkable radioresistance of GSCs has been known to promote radiotherapy failure and therefore is associated with a significantly higher risk of a local tumor recurrence. Moreover, the hyperactive cell cycle checkpoint kinase (Chk) 1 and 2 play a pivotal role in the DNA damage response including radiation and chemical therapy. Based on aforementioned, we hypothesized that knockdown of Chk1 or Chk2 might confer radiosensitivity on GSCs and thereby increases the efficiency of radiotherapy. In this study, we knocked down the expression of Chk1 or Chk2 in human GSCs using lentivirus-delivered short hairpin RNA (shRNA) to examine its effect on the radiosensitivity. After radiation, the apoptosis rate and the cell cycle of GSCs were measured with Flow Cytometry. Compared with control GSCs (apoptosis, 7.82 ± 0.38%; G2/M arrest, 60.20 ± 1.28%), Chk1 knockdown in GSCs increased the apoptosis rate (37.87 ± 0.32%) and decreased the degree of the G2/M arrest (22.37 ± 2.01%). In contrast, the radiosensitivity was not enhanced by Chk2 knockdown in GSCs. These results suggest that depletion of Chk1 may improve the radio-sensitivity of GSCs via inducing cell apoptosis. In summary, the therapy targeting Chk1 gene in the GSCs may be a novel way to treat glioblastoma.

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Loss of ATM/Chk2/p53 Pathway Components Accelerates Tumor Development and Contributes to Radiation Resistance in Gliomas

Cited by 215 publications

References 57 publications

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

In vivo radiation response of proneural glioma characterized by protective p53 transcriptional program and proneural-mesenchymal shift

Effect of 5-Aza-2'-deoxycytidine on SLC22A18 in glioma U251 cells

Knockdown of Checkpoint Kinase 1 Is Associated with the Increased Radiosensitivity of Glioblastoma Stem-Like Cells

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