Lack of correlation between ATM protein expression and tumour cell radiosensitivity

Chan, Doug W.; Gately, Dennis; Urban, Stephan; Galloway, Anne M.; Lees‐Miller, Susan P.; Yen, Tim J.; Allalunis‐Turner, Joan

doi:10.1080/095530098141591

Cited by 65 publications

(28 citation statements)

References 27 publications

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“…A connection also may exist between the levels of DNA-PKcs and ATM. 30 Peng et al 31 demonstrated that the amount or activity of DNA-PKcs influenced ATM expression. In our study, the mRNA levels of ATM, DNA-PKcs, and Ku80 were correlated with one another.…”

Section: Discussionmentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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BACKGROUND.The double‐strand break (DSB) repair capacity has been implicated in the survival of patients in several cancer types. However, little is known about the prognostic importance of the key DSB repair genes—ataxia‐telangiectasia mutated (ATM), DNA‐dependent protein kinase catalytic subunit (DNA‐PKcs), and the Ku heterodimeric regulatory complex 86‐kD subunit (Ku80)—in nonsmall cell lung cancer (NSCLC). To address this issue, the authors determined the messenger RNA (mRNA) expression of these genes in patients NSCLC and assessed their prognostic relevance.METHODS.mRNA expression levels of ATM, DNA‐PKcs, and Ku80 were measured in tumor and adjacent normal tissues from 140 patients with NSCLC by using quantitative real‐time polymerase chain reaction analysis. Then, a Cox proportional hazards regression model and Kaplan‐Meier plots were used to evaluate the association between the tumor:normal (T/N) expression ratios of the 3 genes and the overall survival rate and duration in patients with NSCLC.RESULTS.mRNA expression of ATM and DNA‐PKcs, but not of Ku80, was significantly higher in tumor tissues than in adjacent normal tissues (P = .003 and P < .001, respectively). The high T/N expression ratios of ATM and DNA‐PKcs were associated significantly with a 1.82‐fold increased risk of death (95% confidence interval, 1.05–2.70) and a 2.13‐fold increased risk of death (95% confidence interval, 1.21–3.76), respectively. However, no significant association with risk was observed for Ku80. Kaplan‐Meier analyses revealed that patients with high T/N expression ratios of ATM or DNA‐PKcs had notably shorter median survival than patients with low ratios.CONCLUSIONS.The current findings suggested that the T/N expression ratios of ATM and DNA‐PKcs may be useful for identifying NSCLC patients with a poor prognosis who may benefit from more aggressive therapy. Cancer 2008. ©2008 American Cancer Society.

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Section: Discussionmentioning

confidence: 99%

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Xing

Vaporciyan

et al. 2008

Cancer

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“…MO59J cells that are devoid of DNA-PK also exhibit reduced expression of the ataxia telangiectasia mutated (ATM) protein (43). Although the importance of ATM in signaling the DNA damage response to IR is well established (44,45), the levels of ATM do not correlate with radiosensitivity (43).…”

Section: Nhej Status Influences Cisplatin Radiosensitizationmentioning

confidence: 99%

“…Although the importance of ATM in signaling the DNA damage response to IR is well established (44,45), the levels of ATM do not correlate with radiosensitivity (43). If the synergism between IR and cisplatin involves DNA-PK and NHEJ, the inability to signal to this pathway may also be expected to reduce synergism.…”

Section: Nhej Status Influences Cisplatin Radiosensitizationmentioning

confidence: 99%

Cisplatin Sensitizes Cancer Cells to Ionizing Radiation via Inhibition of Nonhomologous End Joining

Boeckman

Trego

Turchi

2005

Molecular Cancer Research

140

106

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The combination of cisplatin and ionizing radiation (IR) treatment represents a common modality for treating a variety of cancers. These two agents provide considerable synergy during treatment, although the mechanism of this synergy remains largely undefined. We have investigated the mechanism of cisplatin sensitization to IR using a combination of in vitro and in vivo experiments. A clear synergistic interaction between cisplatin and IR is observed in cells proficient in nonhomologous end joining (NHEJ) catalyzed repair of DNA double-strand breaks (DSB). In contrast, no interaction between cisplatin and IR is observed in NHEJ-deficient cells. Reconstituted in vitro NHEJ assays revealed that a site-specific cisplatin-DNA lesion near the terminus results in complete abrogation of NHEJ catalyzed repair of the DSB. These data show that the cisplatin-IR synergistic interaction requires the DNA-dependent protein kinase -dependent NHEJ pathway for joining of DNA DSBs, and the presence of a cisplatin lesion on the DNA blocks this pathway. In the absence of a functional NHEJ pathway, although the cells are hypersensitive to IR, there is no synergistic interaction with cisplatin. (

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“…However, a human glioma cell line, M059J, which is characterized by hypersensitivity to radiation and lack of DNA-PKcs protein, has extremely low levels of ATM protein (21). Reverse transcription-PCR failed to detect a difference in ATM mRNA in M059J and a related cell line with normal DNA-PKcs.…”

Section: Introductionmentioning

confidence: 99%

Deficiency in the Catalytic Subunit of DNA-Dependent Protein Kinase Causes Down-Regulation of ATM

et al. 2005

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Previous reports have suggested a connection between reduced levels of the catalytic subunit of DNA-dependent protein kinases (DNA-PKcs), a component of the nonhomologous DNA double-strand breaks end-joining system, and a reduction in ATM. We studied this possible connection in other DNA-PKcs-deficient cell types, and following knockdown of DNA-PKcs with small interfering RNA, Chinese hamster ovary V3 cells, lacking DNA-PKcs, had reduced levels of ATM and hSMG-1, but both were restored after transfection with PRKDC. Atm levels were also reduced in murine scid cells. Reduction of ATM in a human glioma cell line lacking DNA-PKcs was accompanied by defective signaling through downstream substrates, post-irradiation. A large reduction of DNA-PKcs was achieved in normal human fibroblasts after transfection with two DNA-PKcs small interfering RNA sequences. This was accompanied by a reduction in ATM. These data were confirmed using immunocytochemical detection of the proteins. Within hours after transfection, a decline in PRKDC mRNA was seen, followed by a more gradual decline in DNA-PKcs protein beginning 1 day after transfection. No change in ATM mRNA was observed for 2 days post-transfection. Only after the DNA-PKcs reduction occurred was a reduction in ATM mRNA observed, beginning 2 days post-transfection. The amount of ATM began to decline, starting about 3 days post-treatment, then it declined to levels comparable to DNA-PKcs. Both proteins returned to normal levels at later times. These data illustrate a potentially important cross-regulation between the nonhomologous endjoining system for rejoining of DNA double-strand breaks and the ATM-dependent damage response network of pathways, both of which operate to maintain the integrity of the genome.

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Lack of correlation between ATM protein expression and tumour cell radiosensitivity

Abstract: Variations in the levels of ATM protein are insufficient to explain the differences in cellular radiosensitivity observed in a panel of human malignant glioma cell lines.

Cited by 65 publications

References 27 publications

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Prognostic significance of ataxia‐telangiectasia mutated, DNA‐dependent protein kinase catalytic subunit, and Ku heterodimeric regulatory complex 86‐kD subunit expression in patients with nonsmall cell lung cancer

Cisplatin Sensitizes Cancer Cells to Ionizing Radiation via Inhibition of Nonhomologous End Joining

Deficiency in the Catalytic Subunit of DNA-Dependent Protein Kinase Causes Down-Regulation of ATM

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